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. Author manuscript; available in PMC: 2009 Sep 22.
Published in final edited form as: Pharmacol Ther. 2006 Aug 14;112(3):810–832. doi: 10.1016/j.pharmthera.2006.06.003

Synaptic plasticity and phosphorylation

Hey-Kyoung Lee 1,*
PMCID: PMC2748765  NIHMSID: NIHMS144027  PMID: 16904750

Abstract

A number of neuronal functions, including synaptic plasticity, depend on proper regulation of synaptic proteins, many of which can be rapidly regulated by phosphorylation. Neuronal activity controls the function of these synaptic proteins by exquisitely regulating the balance of various protein kinase and protein phosphatase activity. Recent understanding of synaptic plasticity mechanisms underscores important roles that these synaptic phosphoproteins play in regulating both pre- and post-synaptic functions. This review will focus on key postsynaptic phosphoproteins that have been implicated to play a role in synaptic plasticity.

Keywords: Phosphoproteins, Postsynaptic, Long-term potentiation, Long-term depression, Homeostatic plasticity

1. Introduction

Activity-dependent changes in synaptic connections are considered critical in many of the brain functions, ranging from developmental plasticity, memory formation, recovery of function after injury, drug addiction, to neurodegeneration. Synaptic plasticity can result from both external (i.e. experience) and internal (i.e. developmental) factors, however this review will focus on synapse changes induced by experience, in the form of neural activity. Bidirectional modifications of synaptic strength can be elicited experimentally using electrical stimulation paradigms in diverse set of synapses in various brain regions (Malenka & Bear, 2004), and also has been observed in vivo following learning (Rogan et al., 1997; Rioult-Pedotti et al., 2000) or sensory experience (Sawtell et al., 2003; Clem & Barth, 2006; Goel et al., 2006). It is now recognized that there are largely 2 classes of synaptic plasticity mechanisms that are required for proper neural function. One form of synaptic plasticity operates on specific sets of synapses (i.e. synapse-specific plasticity), while another set is loosely bound together under the terminology “homeostatic plasticity”, which acts on global variables to affect the function of all synapses on a given neuron. Therefore, investigations of the molecular mechanisms of synaptic plasticity require an understanding of the type of plasticity that is being studied.

Alterations in synaptic strength, either by synapse-specific plasticity or homeostatic plasticity, can be mediated by multiple mechanisms. First, changes can be at synaptic loci, both pre- and postsynaptic compartments. Second, it can be mediated by changes in dendritic or axonal excitability. Third, synaptic plasticity can result from alterations in gene expression, again in either pre- or postsynaptic neurons. Lastly, non-neuronal changes can also contribute, for example changes in glial–neuronal interactions or vascular–neuronal interactions. However, discussion of all these topics would be beyond the scope of this review, and thus the following discussion will be limited to how regulation of key postsynaptic proteins contributes to changes in synaptic strength. There are now vast amounts of data, which implicate reversible phosphorylation of synaptic proteins as a potential mechanism for mediating various forms of synaptic plasticity. Most of the results come from studies of synapse-specific plasticity mechanisms, such as long-term potentiation (LTP) and long-term depression (LTD). However, increasing number of recent studies is focusing on understanding the molecular mechanisms of homeostatic plasticity.

2. A brief introduction to synaptic plasticity

It was recognized early on that activity-dependent changes in the efficacy of synapses could be a mechanism for information storage, particularly in learning and memory formation. Donald O. Hebb is credited with the first formulation of a learning rule based on correlated neural activity. He proposed that synaptic connections become stronger when the presynaptic activity triggers action potentials in the postsynaptic neuron (Hebb, 1949). The Hebbian rule was first confirmed 2 decades later by the discovery that brief and intense synaptic activation results in a LTP of synaptic strength in the hippocampus (Bliss & Lomo, 1973). Subsequently, the necessity for an anti-Hebbian rule in which synaptic strength decreases when the activity of the 2 neurons are not correlated was also recognized (Stent, 1973). This was confirmed nearly 2 decades later when several investigators demonstrated that delivering prolonged but weak subthreshold stimulation results in a LTD of synaptic strength in the hippocampus (Fujii et al., 1991; Dudek & Bear, 1992; Mulkey & Malenka, 1992). More recently, premises of both Hebbian and anti-Hebbian mode of synaptic plasticity have been tested by demonstration of spike-timing dependent plasticity (STDP) where the timing between pre- and post-synaptic activity determines the sign of synaptic change (for a review on STDP, see Dan & Poo, 2004). For a more comprehensive historic overview on the 30 years of research on LTP and LTD, readers are referred to volume 358, issue 1432 of the Philosophical Transactions of the Royal Society of London Series B Biological Sciences (Philos Trans R Soc Lond B Biol Sci).

The discovery of LTP and LTD opened the possibility of understanding the basic cellular and molecular mechanisms of synaptic plasticity. It is now clear that several forms of LTP and LTD can be induced in almost all areas of the central nervous system. However, most of our understanding on the molecular mechanisms of synaptic plasticity derives from studies on a specific form of LTP and LTD, which is dependent on N-methyl-d-aspartate (NMDA) receptor activation. Due to the intense research efforts of the last few decades, the basic properties and induction mechanisms of LTP and LTD have been worked out to considerable biophysical and molecular detail. Currently, rapid progress is being made in elucidating the cellular changes that express synaptic plasticity, and how these changes are maintained for a prolonged duration. There is accumulating evidence that changes in protein phosphorylation by various protein kinases and protein phosphatases are involved in either mediating or regulating LTP and LTD expression. This will be elaborated upon in the following section.

It has been appreciated for some time that rapid bidirectional synaptic plasticity mechanisms, such as LTP and LTD, are not sufficient to mediate proper brain function (Bienenstock et al., 1982a; Bear et al., 1987; Abraham & Bear, 1996; Miller, 1996; Turrigiano & Nelson, 2000, 2004). This is due to the fact that LTP and LTD have a built-in positive-feedback mechanism that causes instability in a neural network (for recent reviews on this topic, see Turrigiano & Nelson, 2000, 2004). There are several mechanisms proposed that can provide negative feedback to stabilize synapse-specific synaptic plasticity. One is the “sliding threshold” model, which proposed that the threshold for inducing LTP and LTD “slides” as a function of average postsynaptic activity (Bienenstock et al., 1982b; Bear, 1995). An overall increase in output activity will “slide” the “threshold” to favor LTD induction, while a decrease in average output activity will “slide” the “threshold” to favor LTP induction. A mechanism termed “priming”, where prior history of synaptic activity alters subsequent synaptic plasticity, is also considered to result from “sliding threshold”. Often, the “sliding threshold” model is referred to as “metaplasticity” to emphasize that it is a plasticity mechanism for regulating synaptic plasticity (Abraham & Bear, 1996). A second mechanism of homeostatic plasticity is termed “synaptic scaling”, where chronic increase in input activity “scales down” the strength of all synapses impinging on a neuron, while a persistent decrease in input activity “scales up” all the synapses (Turrigiano et al., 1998; Turrigiano & Nelson, 2004).

“Sliding threshold” or “metaplasticity” is thought to involve changes in the molecular events that regulate LTP and LTD induction mechanisms. For example, changes in NMDA receptor function has been suggested as 1 mechanism for “metaplasticity” at synapses that undergo NMDA receptor-dependent LTP and LTD (Quinlan, Olstein et al., 1999; Quinlan, Philpot et al., 1999; Philpot et al., 2001; Philpot et al., 2003). On the other hand, “synaptic scaling” has been linked to regulation of both α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors (Lissin et al., 1998; O'Brien et al., 1998; Turrigiano et al., 1998; Ju et al., 2004; Thiagarajan et al., 2005) and NMDA receptors (Watt et al., 2000), as well as changes in postsynaptic excitability (Maffei et al., 2004), inhibition (Rutherford et al., 1998), and presynaptic function (Burrone et al., 2002; Thiagarajan et al., 2002, 2005). Regardless of the terminologies and the underlying mechanisms, net effect of homeostatic plasticity is to provide stability to neural networks that constantly undergo synapse-specific modifications.

3. Protein kinases and protein phosphatases involved in synaptic plasticity: a short introduction

Despite divergence in details, there is a general consensus that NMDA receptor-dependent LTP and LTD are triggered by postsynaptic mechanisms. The magnitude and temporal pattern of increase in postsynaptic calcium through NMDA receptors seems to be the key in determining whether LTP or LTD is induced (Cummings et al., 1996; Yang et al., 1999). This is thought to be due to the differential sensitivity of protein kinases and protein phosphatases to calcium increase (Lisman, 1985). Various protein kinases and protein phosphatases have been implicated in synaptic plasticity, and many are in close proximity to NMDA receptors (Husi et al., 2000), ideally suited to mediate the downstream signaling by the activation of this receptor.

The identity of the exact protein kinases and phosphatases required for LTP and LTD is still under debate. For LTP, there is evidence for the involvement of Ca2+/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), cAMP-dependent protein kinase (PKA), cGMP-dependent protein kinase (PKG), casein kinase II (CKII), mitogen-activated protein kinase (MAPK), various tyrosine kinases, and regulation of various protein phosphatases (see Table 1). As for LTD, activity of various protein phosphatases (protein phosphatase 1 [PP1], protein phosphatase 2A [PP2A], protein phosphatase 2B [PP2B, calcineurin]; see Table 1) and regulation of PKA (Brandon et al., 1995; Kameyama et al., 1998) and PKC (Thiels et al., 2000) are implicated.

Table 1.

Protein kinases and protein phosphatases involved in synaptic plasticity

Protein kinase Activation Known synaptic substrates Proposed role for mediating synaptic plasticity
CaMKII Increased activity with TBS (Fukunaga et al., 1993). Increased autophosphorylation at T286 with TBS (Barria, Muller et al., 1997). Increased autophosphorylation at T286 in dendrites with HFS (4×100 Hz, 1 sec, ITI=30 sec) (Ouyang et al., 1997). CaMKII (Lai et al., 1986; Miller & Kennedy, 1986), GluR1 (Barria, Derkach et al., 1997; Mammen et al., 1997), NR2B (Omkumar et al., 1996; Strack et al., 2000), SAP97 (Gardoni et al., 2003; Mauceri et al., 2004), Rabphilin (Fykse et al., 1995), Stargazin (Tomita et al., 2005), Synapsin I (Huttner et al., 1981; Czernik et al., 1987). E-LTP expression (Malenka et al., 1989; Malinow et al., 1989; Silva et al., 1992; Otmakhov et al., 1997; Lee et al., 2000). CaMKII-alpha autophosphorylation on T286 necessary for LTP (Giese et al., 1998). Metaplasticity (Mayford et al., 1995; Elgersma et al., 2002; Zhang et al., 2005). Homeostatic synaptic plasticity (Thiagarajan et al., 2002).
PKA Transient activation after HFS (3×100 Hz, 1 sec (ITI=5 sec)) (Roberson & Sweatt, 1996). GluR1 (Roche et al., 1996), GluR4 (Carvalho et al., 1999), NR1 (Tingley et al., 1997), NR2A (Krupp et al., 2002), Rabphilin (Fykse et al., 1995), Stargazin (Chen et al., 2000; Chetkovich et al., 2002), Synapsin I (Huttner et al., 1981; Czernik et al., 1987). E-LTP expression (Lee et al., 2000; Otmakhova et al., 2000; Skeberdis et al., 2006). L-LTP expression (Matthies & Reymann, 1993; Huang & Kandel, 1994; Qi et al., 1996; Abel et al., 1997). LTP induction during early development (Yasuda et al., 2003; Wikstrom et al., 2003). “Priming” LTP (Oh et al., 2006). “Gating” LTP (Blitzer et al., 1995, 1998). RII-beta subunit involved in LTD (Brandon et al., 1995).
PKC Increased membrane bound PKC 30 min after HFS (1×100 Hz, 1 sec) (Sacktor et al., 1993). Increased membrane bound PKC 1 hr after, but not 1 min after HFS (?) (Akers et al., 1986). Decreased activity following LTD induction in vivo (Thiels et al., 2000). GAP43/Neuromodulin /B-50/F-1 (Aloyo et al., 1983; Akers & Routtenberg, 1985), GluR1 (Roche et al., 1996), GluR2 (Matsuda et al., 1999; Chung et al., 2000; McDonald et al., 2001), GluR4 (Carvalho et al., 1999), MARCKS (Wu et al., 1982; Stumpo et al., 1989), Neurogranin/RC3 (Baudier et al., 1989), NR1 (Tingley et al., 1997; Sanchez-Perez & Felipo, 2005). NR2B (Liao et al., 2001), Stargazin (Tomita et al., 2005). LTP maintenance (Lovinger et al., 1987; Kauer et al., 1988; Reymann, Brodemann et al., 1988; Reymann, Frey et al., 1988; Huang et al., 1992). LTP induction (Huang et al., 1992). PKCgamma necessary for LTP, but not for LTD or DeD (Abeliovich et al., 1993).
PKMzeta Increase in cytosol 30 min after HFS (1×100 Hz, 1 sec) (Sacktor et al., 1993). Decreased in cytosol 30 min after 3 Hz, 5 min stimulation (Hrabetova & Sacktor, 1996). Maintenance of L-LTP (Sacktor et al., 1993; Ling et al., 2002; Serrano et al., 2005). Maintenance of I-LTP (Serrano et al., 2005). Decreased during LTD maintenance (Hrabetova & Sacktor, 1996).
PKG LTP expression (Zhuo et al., 1994). L-LTP expression (Lu et al., 1999). Not involved in LTP (Selig et al., 1996). Not necessary for LTP (Kleppisch et al., 1999).
CKII Transient activation with HFS (2×100 Hz, 0.5 sec (ITI=?)) (Charriaut-Marlangue et al., 1991). GAP43/Neuromodulin (Pisano et al., 1988; Apel et al., 1991), NR2B (Chung et al., 2004). LTP expression (Charriaut-Marlangue et al., 1991).
MAPK Activation of p42 MAPK (ERK2) after HFS (2×100 Hz, 1 sec (ITI=20 sec) repeated 3 times at 10 min intervals) (English & Sweatt, 1996). Increased phosphorylation in dendrites after 5 Hz, 3 sec or 5 Hz, 3 min stimulation (Winder et al., 1999). Synapsin I (Matsubara et al., 1996). L-LTP expression (English & Sweatt, 1997). Not involved in LTP maintenance (English & Sweatt, 1997). Regulates LTP induction (Winder et al., 1999). Involvement in LTP depends on induction protocol used (Selcher et al., 2003). ERK1 not necessary for LTP (Selcher et al., 2001).
Tyrosine kinases Activation of Src with HFS (2×100 Hz, 0.5 sec (ITI=10 sec)) (Lu et al., 1998). GluR2 (Hayashi & Huganir, 2004), NR2A (Zheng et al., 1998; Vissel et al., 2001; Yang & Leonard, 2001), NR2B (Nakazawa et al., 2001; Prybylowski et al., 2005). LTP induction (O'Dell et al., 1991; Huang & Hsu, 1999; Coussens et al., 2000; Huang et al., 2001). Fyn-kinase necessary for LTP expression (Grant et al., 1992). Src and Yes kinase not necessary for LTP (Grant et al., 1992). Src activity required for LTP induction (Lu et al., 1998). LTD induction (Coussens et al., 2000).
PP1 Transient increase in activity following in vivo LTD induction (Thiels et al., 1998). PSD associated CaMKII-alpha (Strack, Barban et al., 1997), GluR1 (Kameyama et al., 1998), stargazin (Tomita et al., 2005). LTD induction (Mulkey et al., 1993). LTD of NMDAR-mediated synaptic transmission (Morishita et al., 2005). Negatively regulates LTP induction (Blitzer et al., 1998; Brown et al., 2000).
PP2A Persistent increase in activity following in vivo LTD induction (Thiels et al., 1998). Decreased activity with TBS (Fukunaga et al., 2000). Soluble CaMKII-alpha (Strack, Barban et al., 1997), GluR1 (Kameyama et al., 1998). LTD induction (Mulkey et al., 1993).
PP2B (calcineurin) GluR1 (Kameyama et al., 1998), NR2A (Krupp et al., 2002), stargazin (Tomita et al., 2005). LTD induction (Mulkey et al., 1994). Calcineurin-alpha specifically involved in depotentiation, but not LTD (Zhuo et al., 1999). Negatively regulates LTP induction (Winder et al., 1998; Malleret et al., 2001). Involved in E-S potentiation (Lu et al., 2000).

Additional abbreviations: DeD (dedepression: LTD reversal), E-LTP (early phase LTP), ERK (extracellular signal-regulated kinase), E-S potentiation (EPSP to spike potentiation), GAP43 (growth associated protein-43), HFS (high frequency stimulation), I-LTP (intermediate-phase LTP), ITI (inter-train interval), L-LTP (late-phase LTP), MARCKS (myristoylated alanine-rich C-kinase substrate), PKMzeta (protein kinase M zeta), TBS (theta burst stimulation).

It seems unlikely, however, that all these molecules are essential for LTP and LTD expression. More likely many of them may play a modulatory or permissive role in the induction or may control the duration of long-term synaptic plasticity (for a more detailed discussion, refer to Sanes & Lichtman, 1999). Indeed in many cases, the involvement of a given protein kinase and protein phosphatase in LTP and LTD appears to depend on the stimulation protocols employed in each study or on the history of prior synaptic activation. Detailed discussions on the many proposed roles of each protein kinases and protein phosphatases in synaptic plasticity are beyond the scope of this review. Readers interested in this topic are referred to some review papers that are focused on this topic (Roberson et al., 1996; Brandon et al., 1997; Ramakers et al., 1997; Blanquet, 2000; Soderling, 2000; Sweatt, 2001; Winder & Sweatt, 2001; Lisman et al., 2002; Nguyen & Woo, 2003; Colbran & Brown, 2004; Kalia et al., 2004; Thomas & Huganir, 2004; Feil et al., 2005). Here I will only provide a brief synopsis on generally agreed functions of some of the protein kinases implicated in synaptic plasticity (see Table 1 for more details).

One particularly fruitful hypothesis on the mechanism of LTP and LTD was proposed by Lisman in 1987. This hypothesis rests on the critical properties of 2 enzymes, CaMKII and PP2B, both of which are activated by Ca2+. CaMKII can phosphorylate itself upon activation and become independent of Ca2+. PP2B can eventually dephosphorylate CaMKII through a protein phosphatase cascade. Importantly, PP2B has a higher affinity for Ca2+/calmodulin than CaMKII. Thus, moderate increases in Ca2+ will preferentially activate PP2B, and eventually dephosphorylate and inactivate CaMKII. Larger increases in Ca2+, on the other hand, will promote CaMKII autophosphorylation. If the proportion of autophosphorylated CaMKII somehow codes for synaptic strength, it follows that moderate increases in Ca2+ will result in LTD, while a large increase in Ca2+ will produce LTP. This hypothesis, coined as the “CaMKII hypothesis” (Lisman, 1994), has since received much attention, and has been vigorously tested by many laboratories as will be discussed later (see Section 6). The “CaMKII hypothesis” has since been updated to include more recent findings on the functional regulation of synaptic AMPA receptors by this protein kinase (Lisman & Zhabotinsky, 2001; Lisman et al., 2002; also see Sections 8 and 9.1 for discussions on the role of CaMKII in regulating synaptic AMPA receptor trafficking during LTP).

Another protein kinase that is thought to be important for LTP is PKA. Initially PKA was proposed as being important for the maintenance of late-phase LTP (L-LTP) (Matthies & Reymann, 1993; Huang & Kandel, 1994; Qi et al., 1996) or “gating” LTP induction by regulating PP1 activity (Blitzer et al., 1995, 1998; Brown et al., 2000). In lieu of recent data on direct phosphorylation and regulation of AMPA receptor subunits (Roche et al., 1996; Benke et al., 1998; Lee et al., 2000; Zhu et al., 2000; Esteban et al., 2003; Lee et al., 2003; Oh et al., 2006; see Section 8 for more details), it seems PKA may also be more directly involved in the expression of LTP. In addition, PKA can regulate NMDA receptor function (Raman et al., 1996; Krupp et al., 2002; Skeberdis et al., 2006; see Section 5.2 for more details), which can also affect the induction of LTP and/or LTD.

As for other protein kinases, their involvement in the early expression phase of LTP is not clear. Consensus for the functional role of PKC, which has been highly discussed as being critical for LTP, is likely for maintaining stable LTP expression (see Table 1). However, in light of its role in regulating NMDA receptors and neurogranin/RC3, PKC could also participate in setting the induction threshold for LTP and/or LTD (see Section 5.2.1 for a more detailed discussion on NMDA receptor regulation and Section 7 for discussions on neurogranin/RC3).

MAPK signaling cascade has also surfaced to participate in LTP, however, its involvement seems to depend partly on the stimulation paradigm used for LTP induction (Table 1). There is a large body of data suggesting that activation of MAPK pathway leads to transcriptional regulation, which may be required for the late-phase LTP (reviewed in Sweatt, 2001; Thomas & Huganir, 2004). More recent findings suggest that MAPK signaling cascade may also operate more locally at synapses (for a detailed discussion on this topic refer to Thomas & Huganir, 2004).

As for tyrosine kinases, Src and Fyn in particular, their major role seems to be on regulation of NMDA receptors as will be discussed later (see Section 5.1 and Table 1). Therefore, they are likely to participate in modulating the threshold for inducing LTP and/or LTD.

4. Phosphoproteins at synapses

Recently, the first large scale mapping of synaptic phosphoproteins was performed by Collins et al. (2005), which employed a combination of mass spectrometry and other high throughput protein analysis methods to generate a list of phosphoproteins present at synapses. This study identified 79 synaptic phosphoproteins, which collectively have 331 phosphorylation sites in total (Collins et al., 2005). However, whether all these phosphoproteins play a role in synaptic plasticity has yet to be confirmed. In addition, the screen may not identify phosphoproteins that are not phosphorylated under basal conditions and only become phosphorylated by synaptic activity or proteins that traffic in and out of synapses dependent on their phosphorylation state. This review will focus on some of the postsynaptic phosphoproteins that have been implicated in synaptic plasticity (Table 1 lists some of the presynaptic phosphoproteins implicated in synaptic plasticity as well).

5. NMDA receptors

Activation of NMDA receptors is critical for the induction of LTP and LTD at diverse sets of synapses (Malenka & Bear, 2004) and is involved in some forms of homeostatic plasticity (Perez-Otano & Ehlers, 2005). Functional importance of NMDA receptors in mediating synaptic plasticity is that they can act as a coincidence detector and allows influx of calcium, which can be used to activate a variety of signaling cascades. The ability of NMDA receptors to act as coincidence detectors of pre- and post-synaptic activity is due to a voltage-dependent relieve of a Mg2+ block of the ion channel (Mayer et al., 1984; Nowak et al., 1984), which allows NMDA receptors to be activated only when presynaptic glutamate release coincides with sufficient postsynaptic depolarization. NMDA receptor channels are formed by tetrameric assembly of 2 obligatory NR1 subunits and 2 NR2 subunits (Cull-Candy et al., 2001). Although majority of the receptors seem to contain a single type of NR2 subunit, it has recently been discussed that NMDA receptors can form triheteromeric receptors with NR1/NR2A/NR2B composition in certain brain areas (Neyton & Paoletti, 2006). There are currently 4 different types of NR2 subunits (i.e. NR2A, NR2B, NR2C, and NR2D) that confer distinct property to the NMDA receptor channel (Cull-Candy et al., 2001). Signaling through NMDA receptors is likely mediated by tightly interacting proteins that comprise a large complex signaling network, often referred to as the “NMDA receptor multiprotein (or macromolecular) complex (NRC)” (Husi et al., 2000) or as the “Hebbosome” (Husi & Grant, 2001). One mode of regulating NMDA receptor function is by phosphorylation of its subunits. Many phosphorylation sites have been identified on the intracellular carboxy-tail of NMDA receptor subunits (Table 2). However, as will be discussed further, some regulation of NMDA receptor function is probably not due to direct phosphorylation of the receptor subunits, but by indirect regulation via other phosphoproteins present in the NMDA receptor macromolecular complex.

Table 2.

Phosphorylation sites on NMDA receptor subunits

Subunit Phosphorylation site Protein kinase Function
NR1 S890 PKC (Tingley et al., 1997), PKCgamma (Sanchez-Perez & Felipo, 2005) Dispersion of surface NR1 (Ehlers et al., 1995; Tingley et al., 1997). Permissive for ER exit (Scott et al., 2003).
S896 PKC (Tingley et al., 1997), PKCalpha (Sanchez-Perez & Felipo, 2005) Permissive for ER exit (Scott et al., 2003).
S897 PKA (Tingley et al., 1997) Necessary for ER exit (Scott et al., 2003).
NR2A Y842 Src (Vissel et al., 2001) Part of YWKL internalization motif (Vissel et al., 2001). Dephosphorylation is responsible for agonist-induced decline in NMDAR current (Vissel et al., 2001). Works together with NR1-Y837 (Vissel et al., 2001).
S900, S929 PKA (Krupp et al., 2002) Glycine-independent desensitization of NR1/NR2A channels (Krupp et al., 2002).
Y1105, Y1267 Src (Zheng et al., 1998) Potentiates NMDAR current by reducing tonic Zn2+ inhibition (Zheng et al., 1998).
Y1292, Y1325 Src (Yang & Leonard, 2001) ?
Y1387 Src (Zheng et al., 1998; Yang & Leonard, 2001) Potentiates NMDAR current by reducing tonic Zn2+ inhibition (Zheng et al., 1998).
S1416 PKC (Gardoni et al., 2001) Inhibits CaMKIIalpha binding (Gardoni et al., 2001).
NR2B Y1252, Y1336, Fyn (Nakazawa et al., 2001) ?
S1303, S1323 PKC (Liao et al., 2001) Potentiates channel current (Liao et al., 2001).
S1303 CaMKII (Omkumar et al., 1996; Strack et al., 2000) Promotes slow dissociation of CaMKII-NR2B complex (Strack et al., 2000).
Y1472 Fyn (Nakazawa et al., 2001; Prybylowski et al., 2005) Part of YEKL internalization motif (Roche et al., 2001; Prybylowski et al., 2005). Stabilizes synaptic NR2B (Roche et al., 2001; Prybylowski et al., 2005). Increase in phosphorylation with LTP (Nakazawa et al., 2001). Dephosphorylation mediates Abeta-dependent endocytosis (Snyder et al., 2005).
S1480 CKII (Chung et al., 2004) Part of PDZ ligand domain (ESDV). Inhibits binding to PSD95 and SAP102 (Chung et al., 2004). Decreases surface expression (Chung et al., 2004).

NMDA receptor regulation has been suggested to be important for metaplasticity (Abraham & Bear, 1996), because this receptor is critical for the induction of LTP and LTD. The degree of NMDA receptor activation and a subsequent increase in postsynaptic Ca2+ concentration usually determines the sign of synaptic plasticity. Therefore, subtle alterations in NMDA receptor function can result in modifying the threshold level of activity required for the induction of LTP or LTD. In accordance with this idea, partial blockade of NMDA receptor or modifying the postsynaptic voltage to allow differential NMDA receptor activation results in sliding the threshold for synaptic plasticity (Cummings et al., 1996; Froemke et al., 2005). This means that partial inhibition of NMDA receptor function can change LTP inducing stimuli to produce LTD, and enhancement of NMDA receptor function can result in LTP with LTD induction protocols. In extreme cases, down-regulation of NMDA receptor function would completely block the induction of LTP and LTD, making synapses resistant to modification by activity. In addition, regulation of NMDA receptor subunit composition may also selectively inhibit LTP or LTD. A couple of studies demonstrated that induction of LTP is prevented by selective inhibition of NR2A containing receptors, while LTD is abolished by blocking NR2B containing receptors (Liu et al., 2004; Massey et al., 2004). However, these findings have recently been contested by several researchers (Hendricson et al., 2002; Barria & Malinow, 2005; Berberich et al., 2005; Weitlauf et al., 2005; Neyton & Paoletti, 2006). Despite the debates on the exact role of each NR2 subunits in synaptic plasticity, NR2A and NR2B display preferential affinity to different postsynaptic density (PSD) proteins (Sans et al., 2000), which may allow for distinct signaling. Therefore, mechanisms that selectively reduce the function of NR2A- or NR2B-containing NMDA receptors have a potential to specifically alter the recruitment of specific signaling pathways during LTP or LTD.

It is important to note that regulation of NMDA receptor by phosphorylation is dependent on the developmental stage of the neurons and the brain region. In addition, there is evidence that prior history of activity may change the subunit composition, adding another level of complexity in terms of understanding the regulation of NMDA receptors. NR1 splice variants, which can be differentially regulated by phosphorylation, show distinct expression pattern in the nervous system (reviewed in Zukin & Bennett, 1995). In addition, a recent study suggests that synaptic activity may regulate the alternative splicing event (Mu et al., 2003). Different NR2 subunits also show distinct temporal and spatial expression pattern (Williams et al., 1993; Monyer et al., 1994). Among the NR2 subunits, NR2A and NR2B are most highly expressed in the forebrain structures, including hippocampus and cortex (Monyer et al., 1994). It is has been demonstrated that synaptic activity can differentially up- or down-regulate these 2 subunits leading to a change in NR2A to NR2B ratio (Quinlan, Olstein et al., 1999; Quinlan, Philpot et al., 1999; Philpot et al., 2001; Barria & Malinow, 2002; Quinlan et al., 2004; Barria & Malinow, 2005). Since NR2A has a shorter duration current compared to NR2B (Monyer et al., 1994), changes in NR2A/NR2B ratio affects the summation of NMDA receptor-mediated synaptic current during repetitive stimulation (Philpot et al., 2001).

5.1. Regulation of NMDA receptor function by tyrosine phosphorylation

It has been appreciated for some time that an ongoing balance between protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) activity seems necessary for maintaining NMDA receptor function. Application of PTK inhibitors (Wang & Salter, 1994; Wang et al., 1996) or introducing exogenous PTP (Wang et al., 1996) depresses NMDA receptor current. In addition, postsynaptic application of exogenous PTK, especially the Src family of PTK (i.e. Src and Fyn), potentiates NMDA receptor current (Wang & Salter, 1994). Most of the Src family of PTK (i.e. Src, Fyn, Yes, and Lyn) are found in the PSD associated with the NMDA receptor (Salter & Kalia, 2004). Among the PTK, Src has surfaced as the major PTK regulating basal NMDA receptor function, and its activity is thought to be counteracted by an ongoing activity of a PTP called striatal enriched tyrosine phosphatase (STEP) (reviewed in Salter & Kalia, 2004). Both Src and STEP are components of the NMDA receptor macromolecular complex (Yu et al., 1997; Pelkey et al., 2002), ideally suited to regulate the channel activity and, ultimately, synaptic plasticity.

5.1.1. Potential mechanisms of Src family of protein tyrosine kinases in mediating enhancement of NMDA receptor function

Evidence supporting a role for Src in regulating NMDA receptor function and synaptic plasticity is abundant. Intracellular application of Src potentiates NMDA receptor current (Wang & Salter, 1994), while a Src-specific inhibitory peptide decreases NMDA receptor function (Yu et al., 1997). Src is activated by LTP-inducing stimulation, and inhibiting Src prevents LTP induction (Lu et al., 1998). Moreover, post-synaptic application of exogenous Src induces synaptic potentiation, that is dependent on NMDA receptor activation, and occludes further LTP (Lu et al., 1998).

Src-mediated potentiation of NMDA receptor function may be due to direct phosphorylation of NMDA receptor subunits. Although the obligatory subunit NR1 does not show detectable tyrosine phosphorylation (Lau & Huganir, 1995), both NR2A and NR2B subunits contain several tyrosine residues on their carboxyl-termini that can be phosphorylated by the Src family of PTK (see Table 2). Src-mediated potentiation of NMDA receptor function is likely mediated by tyrosine phosphorylation of NR2A (Zheng et al., 1998), since Src only potentiates current through NR1/NR2A, but not NR1/NR2B, NR1/NR2C, or NR1/NR2D, expressed in heterologous cells (Kohr & Seeburg, 1996). Several tyrosine phosphorylation sites that are targeted by Src have been identified to potentiate NMDA receptor current by reducing tonic Zn2+ inhibition (Zheng et al., 1998). However, whether this mechanism operates in vivo has been challenged (Xiong et al., 1999). Interestingly, Src-mediated potentiation of NMDA receptor seems to depend on the presence of PSD95 (Liao et al., 2000; Iwamoto et al., 2004), suggesting that other PSD proteins may play a role in mediating this effect.

Surface trafficking of NMDA receptors is also regulated by tyrosine phosphorylation. Surface trafficking of NMDA receptors is regulated by tyrosine-based internalization signal motifs (YXXϕ:ϕ corresponding to a bulky hydrophobic residue) that are present on both NR2A and NR2B (Roche et al., 2001; Vissel et al., 2001; Prybylowski et al., 2005). Tyrosine-based internalization motifs bind to a subunit of adaptor protein AP-2, which recruits them to clathrin coats involved in endocytic vesicle formation (Bonifacino & Traub, 2003). The critical internalization motif for NR2A and NR2B appears to be on different locations of the intracellular C-tail, and the regulation of these 2 subunits occurs via slightly different mechanisms.

In the case of NR2B, YEKL sequence that is located on the distal C-terminal, only a few amino acids upstream of the PSD95 discs-large ZO-1 domain (PDZ) ligand (ESDVCOOH), is critical for internalization (Roche et al., 2001; Prybylowski et al., 2005). The YEKL sequence on NR2B is sufficient to constitutively internalize receptors unless the Y1472 on YEKL sequence is phosphorylated by Fyn or if NR2B is bound to PSD95 via its PDZ ligand (Roche et al., 2001; Prybylowski et al., 2005). It is hypothesized that NR2B binding to PSD95 brings Fyn close to the NR2B YEKL sequence to phosphorylate Y1472 (Prybylowski et al., 2005). This phosphorylation in turn prevents AP-2 adaptors from binding to the YEKL sequence, hence blocking internalization. Increase in tyrosine phosphorylation of NR2B subunits has been observed following LTP induction (Rosenblum et al., 1996; Rostas et al., 1996), which could be the basis for the increased surface NMDA receptor following LTP (Grosshans et al., 2002). However, whether the LTP-induced increase in NR2B tyrosine phosphorylation occurs on Y1472 is unknown. Moreover, the function of the LTP-induced increase in NR2B tyrosine phosphorylation is unclear, since maintenance of LTP is not affected by blocking NMDA receptors (Herron et al., 1986). Also, whether or when NMDA receptor function is potentiated following LTP is debated (Kauer et al., 1988; Clark & Collingridge, 1995; Watt et al., 2004). In any case, synaptic NR2B subunits bound to PSD95 will have an increase in Y1472 phosphorylation, which stabilizes them on the surface. On the other hand, extrasynaptic NMDA receptors are not likely associated with PSD95, which predicts that this population of NMDA receptors may undergo rapid internalization. Consistent with this idea, Roche et al. (2001) observed a developmental decline in constitutive NMDA receptor endocytosis that correlated with developmental increase in PSD95 (Sans et al., 2000).

Unlike the NR2B subunit, endocytosis of NR2A does not depend on the distal YXXϕ motif (Y1454KKM) located on an equivalent position to that of YEKL on NR2B (Lavezzari et al., 2004; Prybylowski et al., 2005). A more proximal sequence on NR2A carboxy-tail (Y842WKL), closer to the last transmembrane domain, has been implicated as an internalization motif (Vissel et al., 2001). Despite the difference in location, internalization of NR2A is also regulated by phosphorylation of the key tyrosine residue (Y842) on the internalization motif, which prevents AP-2 interaction (Vissel et al., 2001). NR2A-Y842 residue is phosphorylated by Src (Vissel et al., 2001). Phosphorylation of Y842 then allows Src to bind, and this competitive binding seems to block AP-2 interaction (Vissel et al., 2001). Interestingly, tyrosine dephosphorylation-induced internalization of NR1/NR2A complex was independent of channel activation, and only required agonist binding (Vissel et al., 2001). This suggests that down-regulation of NMDA receptors can happen in the absence of its channel activity. However, internalization of NR2A may be a bit more complicated, since a more recent study suggests a dileucine motif (L1319L1320) on NR2A may serve as an internalization motif (Lavezzari et al., 2004). How the 2 motifs (Y842WKL and dileucine motifs) interact to regulate NR2A surface expression is currently unknown.

5.1.2. Role of striatal enriched tyrosine phosphatase tyrosine phosphatase in regulating NMDA receptor function

STEP family of non-receptor PTP are highly expressed in the basal ganglia, but also show lower levels of expression in other brain regions, including the hippocampus (Boulanger et al., 1995). Inhibiting STEP enhances basal NMDA receptor current, while postsynaptic injection of exogenous STEP depresses it (Pelkey et al., 2002). In line with its role in counteracting Src activity, blocking Src abolishes the enhancement of NMDA receptor function by STEP inhibition (Pelkey et al., 2002). In accordance with its role in regulating NMDA receptor activity, exogenous STEP application into CA1 neurons prevents LTP induction, while inhibiting STEP produces Src-dependent synaptic potentiation that further occludes LTP (Pelkey et al., 2002). STEP-induced potentiation was blocked by NMDA receptor antagonist, MK801, further suggesting that potentiation of AMPA receptor-mediated synaptic transmission by this enzyme involves the regulation of NMDA receptor activity.

5.2. Regulation of NMDA receptor function by serine phosphorylation

In addition to phosphorylation on tyrosine residues, NMDA receptor subunits can be regulated by phosphorylation on serine residues. PKA and PKC can directly phosphorylate serine residues on NR1, NR2A, and NR2B subunits (Leonard & Hell, 1997; Tingley et al., 1997; Table 2).

5.2.1. Regulation of serine phosphorylation on NR1 subunit

The phosphorylation sites on NR1 have been mapped to serine-890 and serine-896, which are phosphorylated by PKC, and serine-897, which is phosphorylated by PKA (Tingley et al., 1997; Table 2). Phosphorylation of serine-890 by PKC causes dispersion of surface NR1 in heterologous cells (Tingley et al., 1997), which could be a basis for PKC-induced dispersal of synaptic NMDA receptor to extrasynaptic sites (Fong et al., 2002). This contradicts with the more widespread observation that PKC up-regulates NMDA receptor function (reviewed in Ben-Ari et al., 1992). However, it is unlikely that phosphorylation of PKC sites on NR1 subunits plays a role in PKC-mediated potentiation of NMDA receptor currents, because PKC-induced potentiation was still present in mutant receptors either lacking NR1 phosphorylation region (Sigel et al., 1994) or lacking intracellular domains of both NR1 and NR2A (Zheng et al., 1999). PKC-mediated NMDA receptor potentiation may be due to PKC regulation of Src (reviewed in Salter & Kalia, 2004), phosphorylation of NR2B subunit (Liao et al., 2001), or phosphorylation of other regulatory proteins (Lan et al., 2001). Direct phosphorylation of PKC sites on NR1 may have a distinct role in regulating NMDA receptor function.

Different PKC phosphorylation sites on NR1 have been shown to be substrates for specific PKC isoforms (Table 2). For instance, phosphorylation of NR1 serine-896 is preferentially lowered by specific inhibitors for PKC-alpha, while NR1 serine-890 was decreased by a specific peptide inhibitor of PKC-gamma (Sanchez-Perez & Felipo, 2005). PKC-gamma is associated with NR1 (Suen et al., 1998), placing it at an ideal location for regulating NMDA receptors. Application of an mGluR5 (a member of the Group 1 metabotropic glutamate receptor [mGluR]) agonist DHPG (3,5-dihydroxy-phenylglycine) predominantly activates PKC-gamma, but not PKC-alpha or PKC-beta, and increases NR1 serine-890 phosphorylation (Sanchez-Perez & Felipo, 2005). This is interesting in light of the observations that prior mGluR activation prevents subsequent LTP induction (Gisabella et al., 2003; Naie & Manahan-Vaughan, 2004). It is tantalizing to speculate that this effect might be due to PKC-gamma phosphorylation of NR1 serine-890, which would disperse synaptic NMDA receptors to prevent subsequent LTP induction. However, it is important to point out that the effect of Group 1 mGluR activation is quite complex in that activation of this receptor can also enhance LTP induction by a phenomenon called “priming” (Cohen & Abraham, 1996). The seemingly opposite effects of Group 1 mGluR activation on LTP may have to do with the downstream signaling pathway it recruits. The “priming” effect of mGluR activation seems to be linked to phospholipase C (PLC) activation (Cohen et al., 1998) rather than PKC (but see Miura et al., 2002), and depends on up-regulation of translation (Raymond et al., 2000). Moreover, “priming” may not be mediated by direct regulation of NMDA receptor function, since it occurs without changes in basal NMDA receptor synaptic responses (Cohen & Abraham, 1996). As will be discussed later, another PKC substrate, neurogranin/RC3, may be involved in “priming” of LTP (see Section 7).

Recent studies found that NMDA receptor trafficking from endoplasmic reticulum (ER) is dependent on PKC and PKA phosphorylation around the ER retention motif, RXR, present on certain isoforms of NR1 that contain the C1 splicing cassette (Scott et al., 2001, 2003). Serine residues 896 and 897 present on the C1 cassette of NR1 are highly phosphorylated in the microsome fraction that contains ER and Golgi (Scott et al., 2003). The phosphorylation on the serine-897 by PKA is necessary to trigger release from the ER, but the ER exit also depends on the PKC-mediated phosphorylation of other sites (either serine-890 or serine-897) (Scott et al., 2001, 2003). This suggests that a coordinated signaling between PKA and PKC pathways is needed for proper trafficking of NMDA receptors to the plasma membrane. This mechanism may be used to regulate the number of NMDA receptors exiting the ER, which will determine the surface NMDA receptor population. ER exit of NMDA receptors is promoted by alternative splicing of C2′ and C2 splice cassettes present on the NR1 carboxy-terminal (Mu et al., 2003). Interestingly, this splicing event is regulated by synaptic activity (Mu et al., 2003), providing another level of control for this ER exit check point event.

5.2.2. Regulation of serine phosphorylation on NR2 subunits

CaMKII is one of the key NMDA receptor interacting signaling molecules involved in synaptic plasticity. The interaction between active CaMKII and NR2 subunits is thought to be critical for NMDA receptor-dependent LTP expression (Lisman & Zhabotinsky, 2001; Lisman et al., 2002; Barria & Malinow, 2005). This interaction can be modulated by phosphorylation of NR2A and NR2B subunits (Table 2). CaMKII phosphorylation of NR2B-S1303 (Omkumar et al., 1996) promotes dissociation of CaMKII-alpha from NR2B (Strack et al., 2000). This may act as a negative feedback where further recruitment of active CaMKII to synapses causes dissociation of NR2B–CaMKII complexes already present. The interaction between NR2A and CaMKII, which is a weaker interaction than NR2B and CaMKII (Barria & Malinow, 2005), may also be regulated by phosphorylation. Stimulation of slices with a Group 1 mGluR agonist decreases CaMKII-alpha interaction with the NMDA receptor (Gardoni et al., 2001), which may be mediated by PKC phosphorylation of NR2A at S1416 (Gardoni et al., 2001). This result also highlights a potential mechanism for crosstalk between PKC and CaMKII signaling.

NR2 subunits also interact with PSD proteins that contain PDZ domain structures. This interaction occurs by binding of the PDZ proteins to the extreme C-terminus that conforms to a type I PDZ ligand. In the NR2B subunit, serine-1480 present in the PDZ ligand (ESDVCOOH) has been shown to be a phosphorylation site that can regulate binding of PDZ proteins, and endocytosis of NMDA receptors (Chung et al., 2004). NR2B-S1480 is directly phosphorylated by CKII, but requires activation of NMDA receptor and CaMKII upstream (Chung et al., 2004). The consequence of NR2B-S1480 phosphorylation is a reduced interaction with PSD95 and synapse associated protein 102 (SAP102) (Chung et al., 2004). This provides an attractive mechanism for down-regulating synaptic NMDA receptors by activity. It is known that LTP increases CKII activity (Charriaut-Marlangue et al., 1991). This suggests that LTP induction may increase NR2B-S1480 phosphorylation and allow endocytosis of synaptic NMDA receptors. This in turn will prevent further LTP induction, which may be a homeostatic mechanism to prevent run-away potentiation. It is known LTP saturates upon multiple bouts of high frequency stimulation. Whether phosphorylation of NR2B-S1480 is involved in this process will be of interest. Alternatively, or possibly in conjunction with this, NR2B-S1480 phosphorylation may be involved in LTD. It is known that LTD-inducing stimulation not only depresses AMPA receptor-mediated synaptic transmission, but also NMDA receptor-mediated synaptic transmission (termed “LTDNMDAR”) (Xiao et al., 1995; Morishita et al., 2005). Whether the removal of synaptic NMDA receptors via NR2B-S1480 phosphorylation contributes to the LTDNMDAR also awaits confirmation.

6. Ca2+/calmodulin-dependent protein kinase II

CaMKII is a major constituent of the PSD (Kennedy et al., 1983; Walikonis et al., 2000; Peng et al., 2004). CaMKII has received much attention as one of the major protein kinases involved in various forms of synaptic plasticity. CaMKII-alpha and CaMKII-beta are the 2 major isoforms expressed in the brain, which assemble together to make a dodecameric holoenzyme (Kolodziej et al., 2000; Lisman et al., 2002; Colbran & Brown, 2004). CaMKII holoenzyme in vivo exists as either homomeric CaMKII-alpha or heteromeric complexes of CaMKII-alpha and CaMKII-beta (Brocke et al., 1999). Although CaMKII-alpha and CaMKII-beta associate to form a holoenzyme complex, they are expressed differently during development and display slightly different properties and function. For instance, CaMKII-beta is expressed early in development while CaMKII-alpha expression increases dramatically during postnatal development (Bayer et al., 1999). CaMKII-beta, but not the alpha isoform, can regulate neurite extension and synapse formation (Fink et al., 2003). In addition, the ratio of CaMKII-alpha to CaMKII-beta is regulated by activity, such that chronic increase in activity increases CaMKII-alpha/CaMKII-beta ratio, while a persistent decrease activity decreases this ratio (Thiagarajan et al., 2002). Since CaMKII-beta is responsible for attaching CaMKII holoenzyme to the actin cytoskeleton under resting conditions (Shen et al., 1998), changes in CaMKII-alpha/CaMKII-beta ratio will affect subcellular localization of the holoenzyme.

In addition to being a protein kinase, CaMKII is a phosphoprotein and its activity is regulated by autophosphorylation on distinct sites. Autophosphorylation at Threonine-286 (Threonine-287 in CaMKIIbeta), which lies on the autoinhibitory domain of the enzyme, allows constitutive activation of the enzyme (Lai et al., 1986; Miller & Kennedy, 1986; Schworer et al., 1986; Schworer et al., 1988; Thiel et al., 1988). There are also 2 inhibitory phosphorylation sites, Theronine-305 and Threonine-306, which are present on the calmodulin binding region. As will be discussed in more detail, phosphorylation of all these sites has been implicated to play a role in synaptic plasticity.

Vast array of data suggest that CaMKII activity is critical for the induction of NMDA receptor-dependent LTP. Blocking CaMKII activity pharmacologically or via genetic knockout of the CaMKII gene prevents or greatly inhibits LTP (Malenka et al., 1989; Malinow et al., 1989; Silva et al., 1992; Otmakhov et al., 1997; Hinds et al., 1998; Frankland et al., 2001; Elgersma et al., 2002), and CaMKII is activated by LTP inducing stimuli (Fukunaga et al., 1993, 1995; Barria, Muller et al., 1997; Ouyang et al., 1997; De Koninck & Schulman, 1998; Ouyang et al., 1999). Moreover, postsynaptic injection of constitutively active CaMKII can mimic and occlude LTP (Pettit et al., 1994; Lledo et al., 1995).

6.1. Activation and synaptic targeting of CaMKII by autophosphorylation

In the late 1980's, Lisman proposed a model, which later became known as the “CaMKII hypothesis” of synaptic memory storage (Lisman, 1994). The original idea dwells on the observation that CaMKII can be activated by Ca2+ influx through NMDA receptors, which leads to autophosphorylation at Threonine-286 making the enzyme constitutively active (Miller & Kennedy, 1986). This Ca2+-independent CaMKII activity was thought to leave a long-lasting trace or “memory” of the transient increase in intracellular Ca2+ (Lisman, 1989, 1994). Interestingly, CaMKII is preferentially activated by high frequency oscillations of intracellular Ca2+ (De Koninck & Schulman, 1998), making this molecule an ideal candidate that can be activated by high frequency repetitive stimulation often used for inducing LTP. The autophosphorylation of CaMKII at T286 converts the enzyme to become constitutively active by preventing the autoinhibitory domain from blocking the substrate binding site (discussed in Lisman et al., 2002). A persistent increase in T286 autophosphorylation has been observed following LTP inducing protocols by various laboratories (Barria, Muller et al., 1997; Ouyang et al., 1997; Blitzer et al., 1998; Ouyang et al., 1999; Ahmed & Frey, 2005). This autophosphorylation is critical for the induction of NMDA receptor-dependent LTP, since mutating the T286 site completely blocks this form of LTP (Giese et al., 1998; Hardingham et al., 2003). On the other hand, mimicking this autophosphorylation by mutating Threonine-286 to aspartate (CaMKII-T286D) facilitates LTP induction (Bejar et al., 2002). However, this effect is dependent on the expression level of the transgene, where higher expression levels of the CaMKII-T286D actually prevent LTP and shifts the threshold of synaptic plasticity to favor LTD (Mayford et al., 1995; Bejar et al., 2002). This may suggest that CaMKII activation plays a dual role, one for LTP induction and another for regulating the synaptic plasticity threshold. The proportion of CaMKII phosphorylated on T286 may regulate the latter, likely by affecting the inhibitory autophosphorylation as will be discuss in the next section.

Autophosphorylation at T286 not only produces a constitutively active CaMKII, it also allows the holoenzyme to become tightly associated to the PSD on dendritic spines (reviewed by Fink and Meyer, 2002). Attachment of activated CaMKII molecules to the PSD is achieved by its interaction with NMDA receptors at the PSD (Strack & Colbran, 1998; Gardoni et al., 1999; Leonard et al., 1999; Strack et al., 2000; Bayer et al., 2006). Translocation of CaMKII to dendritic spines by NMDA receptor activation has been visualized in neurons by expressing green fluorescence protein (GFP)-CaMKII fusion proteins (Shen & Meyer, 1999; Shen et al., 2000; Otmakhov et al., 2004; Bayer et al., 2006). T286 autophosphorylation is not necessary for translocation of CaMKII to synapses, but it greatly prolongs the PSD localization of the translocated CaMKII (Shen et al., 2000; Bayer et al., 2006). This phenomenon is often described as CaMKII synaptic “trapping” (Shen et al., 2000; Fink & Meyer, 2002). It has been proposed that the recruitment of activated CaMKII (i.e. CaMKII “trapping”) to the PSD provides sites for anchoring AMPA receptors to synapses following LTP induction (Lisman & Zhabotinsky, 2001; Lisman et al., 2002). This hypothesis is supported by the observation that active CaMKII allows for synaptic insertion of AMPA receptors (Hayashi et al., 2000), which will be discussed more in detail in a later section (Section 8).

Autophosphorylation also occurs on the CaMKII-beta subunit at T287(Schworer et al., 1988), which causes dissociation of CaMKII-beta and the CaMKII-beta containing holoenzyme complex from the actin cytoskeleton (Shen & Meyer, 1999). Autophosphorylation of isolated CaMKII-beta is activated by a lower Ca2+/CaM concentration compared to CaMKII-alpha (Brocke et al., 1999). However, autophosphorylation of CaMKII-beta isolated from rat forebrain requires similar Ca2+/CaM concentration to CaMKII-alpha, suggesting that T287 in the beta subunit is probably phosphorylated by alpha subunits present in the same holoenzyme complex (Brocke et al., 1999).

6.2. Inhibitory autophosphorylation of CaMKII

In addition to T286 autophosphorylation, CaMKII is regulated by 2 inhibitory autophosphorylation sites (Threonine-305 and Threonine-306) present in the Ca2+/calmodulin binding site of the enzyme (Hashimoto et al., 1987; Patton et al., 1990). These 2 inhibitory autophosphorylation sites are only exposed after Ca2+/calmodulin complex dissociates following autophosphorylation at T286 (Hashimoto et al., 1987; Patton et al., 1990). The inhibitory autophosphorylation decreases the CaMKII affinity towards Ca2+/calmodulin (Lickteig et al., 1988; Lou & Schulman, 1989; Colbran, 1993), hence prevents further activation of the enzyme by a subsequent increase in intracellular Ca2+. In addition, phosphorylation of the inhibitory sites reduces the CaMKII affinity to the PSD (Strack, Choi et al., 1997; Shen et al., 2000; Elgersma et al., 2002). These inhibitory autophosphorylation sites seem to regulated the threshold for inducing synaptic plasticity rather than being directly involved in the expression mechanisms of LTP or LTD (Elgersma et al., 2002; Zhang et al., 2005).

Interestingly, association of CaMKII to NMDA receptors hinders inhibitory autophosphorylation (Elgersma et al., 2002), and hence can lock the enzyme in an active state (Bayer et al., 2001). This suggests a plausible mechanism to explain how CaMKII may participate in both LTP and metaplasticity. For instance, initial increase in Ca2+ by LTP-inducing stimuli will increase autophosphorylation on T286 and allow CaMKII to bind NMDA receptors, most likely the NR2B subunit (Barria & Malinow, 2005). This interaction between CaMKII and NR2B is critical for LTP expression (Barria & Malinow, 2005). However, if more CaMKII is activated, some will not be able to bind NMDA receptors. And further, these active CaMKII may phosphorylate NR2B subunits (Omkumar et al., 1996) to release pre-bound CaMKII molecules (Strack et al., 2000). All of these changes will promote inhibitory autophosphorylation, hence reducing the pool size of CaMKII that can be activated by subsequent synaptic activity. This in essence will “slide” the threshold for future plasticity.

7. Neurogranin/RC3

Neurogranin is a calmodulin (CaM) binding postsynaptic protein that is also known as RC3, P17 or BICKS (B-50 immunoreactive C-kinase substrate). Neurogranin was identified as a substrate of PKC in the brain (Baudier et al., 1989), and is expressed in postsynaptic compartments of various forebrain structures (Represa et al., 1990; Watson et al., 1992). Subcellular fractionation showed that neurogranin is a soluble protein loosely associated with the PSD (Watson et al., 1994). Interestingly, phosphorylation of neurogranin is regulated by LTP- and LTD-inducing stimuli (Chen et al., 1997; van Dam et al., 2002), and neurogranin knockouts display abnormal synaptic plasticity (Pak et al., 2000; Krucker et al., 2002; Huang et al., 2004).

An interesting key feature of neurogranin is that it binds free calmodulin (Deloulme et al., 1991), and many of its functions can be explained by its ability to regulate the availability of calmodulin in the postsynaptic compartment. Binding of Ca2+-free calmodulin molecules to neurogranin will act to lower the concentration of available calmodulin. Since neurogranins can release calmodulin when intracellular Ca2+ increases, it in essence acts as a calmodulin reservoir that only releases calmodulin when the Ca2+ concentration crosses a certain threshold (discussed in Chakravarthy et al., 1999). Therefore, neurogranin is able to regulate the activity of postsynaptic Ca2+/CaM-dependent enzymes, one of which is CaMKII. In support of this, neurogranin knockouts have less autophosphorylated CaMKII than wildtype mice (Pak et al., 2000; Krucker et al., 2002). The interaction between neurogranin and calmodulin is disrupted by phosphorylation of the calmodulin binding domain on neurogranin by PKC (Gerendasy et al., 1995; Prichard et al., 1999), which provides a link between PKC and CaMKII signaling. Among the various PKC isoforms present at synapses, PKC-gamma is likely crucial for neurogranin phosphorylation in vivo, because depolarization and glutamate-induced neurogranin phosphorylation was absent in PKC-gamma knockout mice (Ramakers et al., 1999).

A current understanding of the role of neurogranin in regulating synaptic plasticity is that it regulates the availability of calmodulin for various Ca2+/CaM-dependent signaling molecules. The release of calmodulin by Ca2+ influx is enhanced when PKC is concurrently activated, providing a synergistic regulation of Ca2+/CaM-dependent signaling. This would suggest that neurogranin will affect the induction processes of synaptic plasticity, which agrees with the observation that neurogranin knockouts display altered threshold for inducing LTP and LTD (Pak et al., 2000; Krucker et al., 2002; Huang et al., 2004). However, it is puzzling that 2 different lines of neurogranin knockouts display an opposite phenotype in regards to sliding the synaptic plasticity threshold. One group reported that neurogranin knockouts display larger LTP and no LTD, consistent with an interpretation that the modification threshold is slid to the left favoring LTP induction (Krucker et al., 2002). Another group demonstrated using an independent line of neurogranin knockouts that LTP is less, while LTD is larger, suggesting a slide in modification threshold to the right (Huang et al., 2004). This difference was speculated to be due to the presence or absence of the N-terminal fragment of neurogranin in the knockouts (Huang et al., 2004). However, it is equally likely that knockout of neurogranin would affect the activity of a network of signaling pathways (Wu et al., 2003); hence a quite different outcome could result from slight biases in each signaling pathways in the background strain.

8. AMPA receptors

AMPA receptors are ionotropic glutamate receptors comprised of 4 different subunits GluR1–4 (or GluR-A through D) that assemble in a combinatorial fashion to form a functional receptor channel (Nakanishi et al., 1990; Wenthold et al., 1992, 1996). These receptors are the major mediator of fast glutamatergic excitatory synaptic transmission in the central nervous system. Structural studies suggest that tetrameric assembly of AMPA receptors are achieved in a dimer-of-dimers fashion (reviewed in Madden, 2002). Different subunits of AMPA receptors display distinct spatial and temporal pattern of expression, and endow specific properties to AMPA receptor complexes. For example, the GluR2 subunit undergoes RNA editing (reviewed in Seeburg & Hartner, 2003), which prevents Ca2+ permeability, contributes to a linear I–V relationship of current flux, and confers insensitivity to intracellular spermine (Boulter et al., 1990; Hollmann et al., 1991; Verdoorn et al., 1991; Keller et al., 1992; Bowie & Mayer, 1995; Donevan & Rogawski, 1995; Washburn et al., 1997). All 4 subunits of AMPA receptors have several identified phosphorylation sites on their intracellular carboxy termini that regulate their function (reviewed in Song & Huganir, 2002), and many more are currently being characterized (Lee et al., 2002; Boehm et al., 2006; Table 3). Due to the essential role of AMPA receptors in mediating synaptic transmission, many of its phosphorylation sites seem to play a role in mediating various forms of synaptic plasticity.

Table 3.

Phosphorylation sites on AMPA receptor subunits

Subunit Phosphorylation site Protein kinase Identified functions
GluR1 S818 PKC (Boehm et al., 2006) Phosphorylation is necessary and sufficient for GluR1 synaptic insertion by LTP (Boehm et al., 2006).
S831 CaMKII (Barria, Derkach et al., 1997; Mammen et al., 1997), PKC (Roche et al., 1996) Increases single channel conductance of homomeric receptors (Derkach et al., 1999; Oh & Derkach, 2005). Persistent increase following LTP (Barria, Muller et al., 1997; Lee et al., 2000). Dephosphorylation after depotentiation (Lee et al., 2000). Can substitute for S845 in mediating LTP (Lee et al., 2003; Lee et al., 2004). Homeostatic plasticity (Goel et al., 2006).
T840 PKC (Lee et al., 2002) Highly phosphorylated in the hippocampus under basal conditions (Lee et al., 2002).
S845 PKA (Roche et al., 1996) Increases mean open probability of channel (Banke et al., 2000). Persistent dephosphorylation following LTD (Kameyama et al., 1998; Lee et al., 1998; Lee et al., 2000; Brown et al., 2005). Necessary for LTD expression (Lee et al., 2003; Lee et al., 2004). Increase in phosphorylation after de-depression (Lee et al., 2000). Necessary for insertion into synapses with LTP induction (Esteban et al., 2003). Can substitute S831 for mediating LTP (Lee et al., 2003; Lee et al., 2004). Regulates AMPA receptor recycling (Ehlers, 2000). Homeostatic plasticity (Goel et al., 2006).
GluR2 Y842 Src (Hayashi & Huganir, 2004) Phosphorylation decreases binding to GRIP (Hayashi & Huganir, 2004). Phosphorylation is necessary for NMDA-induced internalization (Hayashi & Huganir, 2004).
S863 PKC (McDonald et al., 2001) Not been characterized.
S880 PKC (Matsuda et al., 1999; Chung et al., 2000; McDonald et al., 2001) Decreases binding to GRIP and favors interaction with PICK1 (Matsuda et al., 1999; Chung et al., 2000). Increases following LTD in vitro (Kim et al., 2001). Decreases following LTD in vivo (Thiels et al., 2002). Necessary and sufficient for LTD (Seidenman et al., 2003).
GluR4 T830 PKC (Carvalho et al., 1999) Increases surface expression in heterologous cells (Correia et al., 2003).
S842 PKA (Carvalho et al., 1999) Necessary for spontaneous activity-driven synaptic insertion (Esteban et al., 2003).

8.1. Phosphorylation of GluR1 subunit

GluR1 is one of the more abundantly expressed subunit of AMPA receptors in hippocampal and neocortical neurons (Martin et al., 1993; Wenthold et al., 1996). Most of the phosphorylation on GluR1 occurs on serine and threonine residues (Blackstone et al., 1994; Roche et al., 1996; Mammen et al., 1997), but tyrosine phosphorylation has also been observed under certain circumstances (Moss et al., 1993; Wu et al., 2004; Table 3). There are several characterized phosphorylation sites on the intracellular carboxy-terminal of GluR1 (Roche et al., 1996; Barria, Derkach et al., 1997; Mammen et al., 1997; Lee et al., 2002; Boehm et al., 2006). Among these, serine-831 and serine-845 have been implicated to mediate the expression of LTP and LTD (Barria, Muller et al., 1997; Kameyama et al., 1998; Lee et al., 1998, 2000, 2003). Phosphorylation on GluR1-S831 is mediated by PKC and CaMKII (Roche et al., 1996; Barria, Derkach et al., 1997; Mammen et al., 1997), while GluR1-S845 is phosphorylated by PKA (Roche et al., 1996). Phosphorylation on both of these residues can enhance current through AMPA receptor channels, albeit via distinct mechanisms (Derkach et al., 1999; Banke et al., 2000).

Phosphorylation of both GluR1-S831 (Barria, Muller et al., 1997; Lee et al., 2000, 2003) and GluR1-S845 (Lee et al., 2000, 2003; Esteban et al., 2003) has been suggested to mediate LTP expression. Interestingly, the specific phosphorylation site involved seems to depend on the prior history of synaptic activity (Lee et al., 2000). Consistent with these observations, LTP was significantly reduced in adult mice lacking the 2 phosphorylation sites (Lee et al., 2003). However, that some LTP is still present in mice lacking both S831 and S845 phosphorylation sites indicate that phosphorylation events are perhaps not critical for LTP, but may be required for stabilizing LTP (Lee et al., 2003; for more discussion, see Lee, 2006). Taken together with the results demonstrating that adult GluR1 knockout mice do not display LTP (Zamanillo et al., 1999; Mack et al., 2001), this suggests that there are at least 2 components to LTP in adults: one that depends on the presence of GluR1, and another that is dependent on the phosphorylation of the subunit. More recently, mice lacking only S831 or S845 phosphorylation sites were characterized, and preliminary results showed quite normal LTP in both lines (Lee et al., 2004). This suggests that while phosphorylation of S831 and S845 on GluR1 are critical to maintain stable LTP, one or the other is probably sufficient to mediate this function.

The exact role of GluR1-S831 phosphorylation in LTP is unclear at this point. Phosphorylation of GluR1-S831 by CaMKII increases single channel conductance (Derkach et al., 1999), hence it was initially thought to mediate the observed increase in AMPA receptor conductance following LTP induction (Benke et al., 1998; Poncer et al., 2002; Luthi et al., 2004). However, a recent study demonstrated that GluR1-S831 mediated increase in single channel conductance is absent when GluR1 is present with GluR2 in a heteromeric complex (Oh & Derkach, 2005). Since the majority of native AMPA receptors are GluR1/GluR2 heteromers (Wenthold et al., 1996), GluR1-S831 phosphorylation dependent increase in channel conductance likely plays a relatively minor role. This may explain the neuron-to-neuron variability in observing increases in AMPA receptor conductance following LTP (Benke et al., 1998; Luthi et al., 2004). In any case, this exemplifies the importance of potential interaction between different subunits in regulating AMPA receptor function, and that even the same phosphorylation site can affect GluR1-containing AMPA receptors differently depending on whether they are assembled in homomeric or heteromeric complexes. It is unlikely that GluR1-S831 is involved in LTP by regulating synaptic insertion of AMPA receptors, because GluR1 lacking S831 phosphorylation site (S831A mutation) was still able to insert into synapses in a CaMKII-dependent manner (Hayashi et al., 2000). This suggests that CaMKII may act on other PSD proteins to mediate the synaptic insertion of GluR1 containing AMPA receptors following LTP. One potential candidate PSD protein is synapse associated protein 97 (SAP97) as will be discussed later (see Section 9.1).

Initial reports on the involvement of GluR1-S845 in synaptic plasticity showed that dephosphorylation of this residue is associated with LTD (Kameyama et al., 1998; Lee et al., 1998, 2000), and also necessary for induction of LTD (Lee et al., 2003). More recently, phosphorylation of GluR1-S845 was shown to be critical for activity-dependent insertion of AMPA receptors following LTP (Esteban et al., 2003), which may be via increasing extrasynaptic pool of GluR1 (Oh et al., 2006). Therefore, reversible regulation of GluR1-S845 seems to be involved in mediating bidirectional synaptic plasticity. Basal phosphorylation of GluR1-S845 at synapses seems to rely on A-kinase anchoring protein 79/150 (AKAP79/150) (Tavalin et al., 2002), which brings PKA in close proximity to the receptors by binding to a GluR1 interacting molecule SAP97 (Colledge et al., 2000). In accordance with this, disrupting PKA binding to AKAP79/150 produces a rundown of AMPA receptor current (Rosenmund et al., 1994; Snyder et al., 2005), and occludes further LTD induction (Snyder et al., 2005). A recent study demonstrated that LTD induction dissociates AKAP79/150 from AMPA receptor complex (Smith et al., 2006), which could further favor dephosphorylation of GluR1-S845.

The mechanisms by which dephosphorylation of GluR1-S845 mediates LTD is likely through affecting AMPA receptor endocytosis. In support of this idea, dephosphorylation of GluR1-S845 has been associated with AMPA receptor internalization following LTD (Lee et al., 2003; Brown et al., 2005). Whether GluR1-S845 dephosphorylation is transient or persistent seems to determine if the internalized AMPA receptors will recycle back to the plasma membrane or trafficked to lysosome for degradation, respectively (Ehlers, 2000). In line with this, LTD is associated with a persistent dephosphorylation of GluR1-S845 (Lee et al., 1998, 2000) and a reduction in synaptic AMPA receptor amount (Heynen et al., 2000), which could be due to degradation of the internalized receptors. Endocytosis of AMPA receptors following LTD has also been shown to rely on GluR2 subunit, suggesting a potential interaction between these 2 subunits in regulating LTD expression (see Section 8.2 for further discussions).

Recently several additional phosphorylation sites on GluR1 have been identified and characterized (Lee et al., 2002; Boehm et al., 2006). Among these, GluR1-S818 seems like an additional regulatory site for synaptic plasticity. Preliminary results showed that this site is phosphorylated by PKC and increased by LTP (Boehm et al., 2006). In addition, increasing phosphorylation by PKC or a mutation that mimics phosphorylation of S818 drives GluR1 into synapses, while a mutation that prevents phosphorylation blocks LTP (Boehm et al., 2006).

8.2. Phosphorylation of GluR2 subunit

GluR2 is a key subunit, which renders the AMPA receptor channel impermeable to Ca2+ and confers specific biophysical properties (reviewed in Tanaka et al., 2000). There are several serine phosphorylation sites (S863 and S880) mapped on the intracellular carboxy-terminal of GluR2 that are phosphorylated by PKC (Matsuda et al., 1999; Chung et al., 2000; McDonald et al., 2001; Table 3). Among these, serine-880 has been implicated to play a role in synaptic plasticity. GluR2-S880 is part of the extreme carboxy-terminal PDZ ligand sequence (SVKICOOH), which binds 2 groups of PDZ proteins depending on its phosphorylation state. When unphosphorylated at S880, GluR2 can interact with PDZ domains of glutamate receptor interacting protein (GRIP)/ABP (AMPA receptor binding protein) or protein interacting with C-kinase-1 (PICK-1) (Matsuda et al., 1999; Chung et al., 2000). On the other hand, phosphorylated S880 allows preferential binding to PICK-1 (Matsuda et al., 1999; Chung et al., 2000). Interaction between GluR2 and GRIP family of proteins has been shown to stabilize AMPA receptors at synaptic locations (Dong et al., 1997; Srivastava et al., 1998; Wyszynski et al., 1999; Osten et al., 2000) or intracellular pools (Daw et al., 2000; Braithwaite et al., 2002). On the other hand, interaction of S880 phosphorylated GluR2 to PICK-1 has been demonstrated to either promote endocytosis of the receptors (Chung et al., 2000; Iwakura et al., 2001; Perez et al., 2001; Terashima et al., 2004; Lu and Ziff, 2005) or allow trafficking of receptors to the plasma membrane (Daw et al., 2000; Gardner et al., 2005). Therefore, regulation of the GluR2-S880 phosphorylation site can critically change the function of AMPA receptors by altering its interaction with GRIP and PICK-1.

There is evidence suggesting that GluR2-S880 phosphorylation is critical for LTD expression in hippocampal CA1 pyramidal neurons. Postsynaptic injection of phospho-peptides (or peptides that mimic S880 phosphorylation) that can compete with GluR2 in binding with PICK-1 prevents LTD expression, while injecting non-phosphopeptides that will predominantly disrupt interaction with GRIP does not (Kim et al., 2001; Seidenman et al., 2003; but see Daw et al., 2000). In addition, transfection of mutant GluR2 subunits that mimic phosphorylation of S880 produces synaptic depression that occludes further LTD expression, while transfection of mutant GluR2 subunits that prevents S880 phosphorylation blocks LTD (Seidenman et al., 2003).

However, it is unclear at this moment how a GluR2-S880 mediated endocytosis mechanism acts with GluR1-S845 dephosphorylation dependent mechanism to express LTD. Since both mechanisms seem to be necessary for LTD expression, it is likely that they act sequentially to mediate LTD. One possibility is that LTD induction triggers AMPA receptor endocytosis by a GluR2-dependent mechanism, and a subsequent dephosphorylation of GluR1 subunit may occur to prevent the receptors from recycling back to synapses. On the other hand, LTD induction may first trigger dephosphorylation of GluR1, which may then acts to unleash the GluR2-mediated endocytosis mechanism to express LTD (for a more detailed discussion see Lee, 2006).

GluR2 is also phosphorylated on a tyrosine residue (Y842) by Src (Hayashi & Huganir, 2004). Src-induced phosphorylation of GluR2-Y842 causes a decrease in GRIP binding, while not affecting PICK-1 interaction with GluR2 (Hayashi & Huganir, 2004). This implies that GluR2-Y842 phosphorylation should also play a role in GluR2 internalization, similar to GluR2-S880. In accordance, a mutation that prevents phosphorylation of Y842, blocks AMPA- and NMDA-induced internalization of GluR2 (Hayashi & Huganir, 2004). These results underscore the importance of crosstalk between serine/threonine protein kinase systems and tyrosine phosphorylation signaling in regulating AMPA receptor mediated synaptic plasticity.

8.3. Phosphorylation of GluR3 and GluR4 subunits

GluR3 and GluR4 are not as highly expressed in the adult forebrain structures as compared to GluR1 and GluR2 subunits (Petralia & Wenthold, 1992; Martin et al., 1993). However, they do contain homologous phosphorylation sites corresponding to those on GluR1 and GluR2, which have been implicated in synaptic plasticity mechanisms (reviewed in Song & Huganir, 2002). The intracellular carboxy-domain of GluR3 displays sequence homology to GluR2, including a phosphorylation site on the extreme C-tail PDZ ligand region. Since the PDZ ligand of GluR3 is the same sequence as that of GluR2, it suggests that phosphorylation of GluR3 may also allow regulate its interaction with PDZ proteins. However, there is no direct demonstration of the involvement of GluR3 phosphorylation in synaptic plasticity.

Expression of GluR4 in the hippocampus is limited during early postnatal period of development (Zhu et al., 2000; for contradictory results, see Kolleker et al., 2003), and can be inserted into synapses by spontaneous activity (Zhu et al., 2000). Intracellular domain of GluR4 subunits shows some homology to GluR1, and several phosphorylation sites have been mapped to this region, some of which are equivalent to GluR1 phosphorylation sites discussed previously. GluR4-S842 is phosphorylated by PKA in vivo (Carvalho et al., 1999), while T830 has been identified as a PKC target (Carvalho et al., 1999; Table 3). In the hippocampus, PKA activity was shown to insert GluR4 homomeric receptors to synapses that is dependent on S842 (Esteban et al., 2003).

If GluR4-dependent mechanisms are dominant during early development, it suggests that the LTP mechanism changes as the animals mature. This is consistent with reports demonstrating that signaling pathways involved in LTP indeed changes during development (Wikstrom et al., 2003; Yasuda et al., 2003; Palmer et al., 2004). Especially, the observation that LTP is PKA-dependent, but CaMKII-independent, at early postnatal ages (Wikstrom et al., 2003; Yasuda et al., 2003) supports the role of PKA-dependent GluR4 phosphorylation in mediating LTP during the early developmental period. Taken together with the findings that GluR1 knockout mice or GluR1 phosphorylation site mutants show normal LTP when young (Jensen et al., 2003; Lee et al., 2003), these results suggest that the LTP mechanism changes from a PKA-GluR4 dependent mechanism to a CaMKII-GluR1 dependent mechanism during development.

9. Glutamate receptor associated phosphoproteins in the postsynaptic density

9.1. Synapse associated protein 97

SAP97 is a member of the membrane-associated guanylate kinase (MAGUK) protein family, which act as scaffolding proteins for organizing postsynaptic molecules, including ionotropic glutamate receptors. Similar to other members of the MAGUK proteins, SAP97 has 3 PDZ domains, 1 Src homology domain (SH3) domain, and a guanylate kinase (GK) domain. The PDZ domains of SAP97 interact with the extreme GluR1 carboxy-tail, which has a type I PDZ ligand motif (-TGLCOOH) (Leonard et al., 1998; Colledge et al., 2000; Cai et al., 2002), and the carboxy-tail of NR2A, which also has a PDZ ligand motif (-SDVCOOH) (Bassand et al., 1999; Gardoni et al., 2003). SAP97 is known to interact mainly with the intracellular population of AMPA receptors present in the early biosynthetic pathways (Sans et al., 2001), however, it is also co-localized at postsynaptic loci together with GluR1 (Valtschanoff et al., 2000).

Two CaMKII phosphorylation sites have been mapped on SAP97: one is serine-39, which is located on the N-terminal L27 domain (Mauceri et al., 2004), and the other is serine-232 within the PDZ1 domain (Gardoni et al., 2003). Despite being phosphorylated by the same enzyme, these 2 sites seem to mediate different functions. Phosphorylation of serine-39 residue is necessary and sufficient to traffic SAP97 into spines, as well as for trafficking GluR1 subunit to spines (Mauceri et al., 2004). These data are consistent with a role of SAP97 in mediating LTP. A current hypothesis for LTP expression put forth by Lisman proposed SAP97 to be a member of an “AMPA channel anchoring assembly”, which is a protein complex that mediates insertion of AMPA receptors to synapses in a CaMKII-dependent fashion (Lisman et al., 2002). SAP97 fits nicely to this role, since it can bind GluR1 subunit of AMPA receptors and deliver them to spines upon phosphorylation of serine-39 by CaMKII.

In addition to trafficking AMPA receptors to synapses, CaMKII phosphorylation of SAP97 can regulate NMDA receptors via phosphorylation of serine-232. CaMKII phosphorylation of this site disrupts the interaction of SAP97 with NR2A subunit without affecting its interaction with AMPA receptor GluR1 subunit (Gardoni et al., 2003). This is thought to be a mechanism to release NR2A from SAP97 upon delivery to the PSD, where CaMKII may be highly active (Gardoni et al., 2003). If this is a mechanism for activity-dependent delivery of NR2A to synapses, this could be involved in “sliding threshold” type of metaplasticity, where an activity-dependent switch from NR2B to NR2A has been proposed to slide the threshold to prevent further LTP induction (Quinlan, Olstein et al., 1999; Quinlan, Philpot et al., 1999; Philpot et al., 2001). Whether the 2 CaMKII phosphorylation sites on SAP97 work in harmony or are mutually exclusive in regulating function is currently unknown.

9.2. Stargazin

Stargazin is a member of transmembrane AMPA receptor regulatory proteins (TARP), which interact with AMPA receptors (Tomita et al., 2003). Recent structural analysis of native AMPA receptors reveal stargazin as an integral part of the AMPA receptor channel (Fukata et al., 2005; Nakagawa et al., 2005; Nicoll et al., 2006). Assembly of stargazin with AMPA receptors greatly enhances current flow through the channel (Priel et al., 2005; Tomita et al., 2005). More over, a line of mice lacking stargazin by a spontaneous mutation (called “stargazer” mice) lack functional AMPA receptors in the cerebellum (Hashimoto et al., 1999; Chen et al., 2000), which correlates with motor deficits (i.e. ataxia) (reviewed in Letts, 2005; Nicoll et al., 2006). In the forebrain structures, other stargazin related TARPs are thought to be involved in regulating AMPA receptor function. For example, gamma-3 is highly expressed in the cortex, while gamma-8 is almost exclusively expressed in the hippocampus (Tomita et al., 2003).

Stargazin has a PDZ ligand region (-TTPVCOOH) that interacts with PSD95 (Chen et al., 2000). A mutant stargazin lacking the PDZ ligand is able to traffic AMPA receptors to plasma membrane, but fails to incorporate them into synapses (Chen et al., 2000). Similar results were seen in hippocampal neurons of a knockout mouse lacking TARP gamma-8 (Rouach et al., 2005). Moreover a direct interaction of stargazin with PSD95 is necessary for increasing synaptic AMPA receptor content (Schnell et al., 2002). Therefore, TARPs seem to mediate AMPA receptor trafficking by 2 separate means: first, by bringing the receptors to the plasma membrane, which does not require its interaction with PSD95, and second is by localizing the surface receptors to synapses by binding to PSD95.

Recent studies demonstrated that stargazin can be phosphorylated (Chetkovich et al., 2002; Choi et al., 2002; Tomita et al., 2005). Phosphorylation of stargazin by PKA occurs on Threonine-321, which prevents PSD95 binding (Chetkovich et al., 2002; Choi et al., 2002). This predicts that PKA phosphorylation of stargazin would disrupt AMPA receptor synaptic localization, which is consistent with the observation that a mutation mimicking T321 phosphorylation decreases AMPA receptor-mediated synaptic current (Chetkovich et al., 2002). On the other hand, phosphorylation of several conserved serine residues on the cytoplasmic domain of TARP enhances synaptic trafficking of AMPA receptors without affecting surface delivery of these receptors (Tomita et al., 2005). Phosphorylation of these serine residues is high under basal conditions, and their regulation is critical for LTP and LTD (Tomita et al., 2005). Phosphorylation of these conserved serine residues is likely mediated by PKC and CaMKII, while dephosphorylation depends on PP1 and PP2B activity (Tomita et al., 2005).

10. Concluding remarks

Phosphorylation is a major mechanism to rapidly and reversibly regulate function of a vast number of cellular proteins. Neurons are no exception, and many of the synaptic proteins, both pre- and post-synaptic, are phosphoproteins. Regulation of these phosphoproteins is likely important for synaptic function and plasticity. Regulation of various protein kinases and protein phosphatases by neuronal activity allows for coordinated control of synaptic phosphoproteins. However, we are far from an understanding of how the orchestrated changes in the activity of diverse protein kinases and protein phosphatases translate into the proper regulation of synaptic proteins that is required to mediate specific changes in synaptic function. Many of the challenges in our understanding are due to the fact that signaling pathways crosstalk with each other, which adds another level of complexity. Also, the signaling pathways recruited by neural activity seem to depend on the pattern of synaptic activity, presence of various neuromodulators, and on the prior history of synaptic activity. Despite the complexity of signaling pathways involved, our understanding of the downstream effectors might provide us with guide lights in which we can begin to explore the exquisite regulation of synaptic function by neural activity.

Acknowledgments

The author would like to thank Dr. A. Kirkwood for helpful discussions and J. Silva for help on the manuscript.

Abbreviations

AKAP79/150

A-kinase anchoring protein 79/150

AMPA

α-amino-3-hydroxy-5-methyl-4-isoxazole propionate

CaMKII

Ca2+/calmodulin-dependent protein kinase II

CKII

casein kinase II

ER

endoplasmic reticulum

GFP

green fluorescence protein

GRIP

glutamate receptor interacting protein

LTD

long-term depression

LTP

long-term potentiation

MAPK

mitogen-activated protein kinase

mGluR

metabotropic glutamate receptor

NMDA

N-methyl-d-aspartate

PICK-1

protein interacting with C-kinase-1

PDZ

PSD95 discs-large ZO-1

PKA

cAMP-dependent protein kinase

PKC

protein kinase C

PKG

cGMP-dependent protein kinase

PLC

phospholipase C

PP1

protein phosphatase 1

PP2A

protein phosphatase 2A

PP2B

protein phosphatase 2B or calcineurin

PSD

postsynaptic density

PTK

protein tyrosine kinase

PTP

protein tyrosine phosphatase

SAP97

synapse associated protein 97

SAP102

synapse associated protein 102

SH3

Src homology domain 3

STDP

spike-timing dependent plasticity

STEP

striatal enriched tyrosine phosphatase

TARP

transmembrane AMPA receptor regulatory protein

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