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. 2024 Apr 15;16(2):165–171. doi: 10.1007/s12551-024-01184-8

Calcium-permeable AMPA and kainate receptors of GABAergic neurons

V P Zinchenko 1, L P Dolgacheva 1, S T Tuleukhanov 2,✉
PMCID: PMC11078900  PMID: 38737208

Abstract

This Commentary presents a brief discussion of the action of glutamate calcium permeable receptors present with neurons on the release of the neurotransmitter gamma-aminobutyric acid (GABA). In particular, Glutamate sensitive Kainic Acid Receptors (KARs) and α-Amino-3-hydroxy-5-Methyl-4-isoxazole Propionic Acid Receptor (AMPARs) are Na+ channels that typically cause neuronal cells to depolarize and release GABA. Some of these receptors are also permeable to Ca2+ and are hence involved in the calcium-dependent release of GABA neurotransmitters. Calcium-permeable kainate and AMPA receptors (CP-KARs and CP-AMPARs) are predominantly located in GABAergic neurons in the mature brain and their primary role is to regulate GABA release. AMPARs which do not contain the GluA2 subunit are mainly localized in the postsynaptic membrane. CP-KAR receptors are located mainly in the presynapse. GABAergic neurons expressing CP-KARs and CP-AMPARs respond to excitation earlier and faster, suppressing hyperexcitation of other neurons by the advanced GABA release due to an early rapid [Ca2+]i increase. CP-AMPARs have demonstrated a more pronounced impact on plasticity compared to NMDARs because of their capacity to elevate intracellular Ca2+ levels independently of voltage. GABAergic neurons that express CP-AMPARs contribute to the disinhibition of glutamatergic neurons by suppressing GABAergic neurons that express CP-KARs. Hence, the presence of glutamate CP-KARs and CP-AMPARs is crucial in governing hyperexcitation and synaptic plasticity in GABAergic neurons.

Keywords: Calcium-permeable kainate and AMPA receptors, GABAergic neurons, Neurodegenerative diseases, Synaptic plasticity

Introduction

The focus of this Commentary is on calcium-permeable kainate and AMPA receptors (CP-KARs and CP-AMPARs). Glutamate KARs and AMPARs are Na+ channels that typically cause the cell to depolarize with a subset of these receptor types being permeable to Ca2+. This Commentary discusses the relevant changes in the channel permeability, function, and where these CP-KARs and CP-AMPARs are located in synapses and neurons. A detailed account of the targets and expression of CP-KARs and CP-AMPARs in GABAergic neurons is given. Acting both through ionotropic receptors (NMDARs—N-methyl-D-aspartate receptors, AMPARs—α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptors and KARs) and metabotropic receptors (also known as G-protein-coupled receptors), glutamate is the primary excitatory neurotransmitter in the mammalian brain. NMDA receptors carry Ca2+ ions, triggering the neurotransmitters release. However, a fraction of the KA and AMPA receptors are also calcium-permeable, being also involved in calcium-dependent release of neurotransmitters (Park et al. 2021; Zinchenko et al. 2021). Since CP-KARs and CP-AMPARs are predominantly located in GABAergic neurons, their primary role is to regulate GABA release. The evidence from recent years has shown that GABAergic neurons expressing CP-KARs and CP-AMPARs respond to excitation earlier and faster, suppressing hyperexcitation of other neurons by the GABA release due to an early rapid [Ca2+]i increase (Zinchenko et al. 2020, 2021). Also, GABAergic neurons expressing CP-AMPARs are involved in the disinhibition of glutamatergic neurons due to suppression of GABAergic neurons expressing CP-KARs. The study of both CP-KARs and CP-AMPARs is therefore very important because these types of receptors are fundamental to both the plasticity and the death of neurons, and as such we discuss the relevant aspects of each of these two types of receptors in turn.

AMPA receptors, subunit composition, editing, Ca2+permeability

AMPA receptors are commonly regarded as membrane-depolarizing channels that depolarize the membrane due to permeability for Na+, which provides the passage of excitatory signals through neuronal synapses, activation of voltage-dependent calcium channels, the removal of Mg2+ block from NMDA–receptors (Mayer et al. 1984). AMPARs function as tetramers which are constructed from dimeric combinations of four main subunits, namely GluA1–4. The functional properties of AMPAR channels are determined largely by the composition of subunits and regulated by post-transcriptional RNA editing, post-translation modification, and accessory proteins (Barbon and Barlati 2011). The mRNA editing prior to translation is carried out by the ADAR protein (RNA adenosine deaminase). In this case, the CAG triplet is replaced by CIG (adenosine is replaced by inosine), and in the channel subunit structure, glutamine in the 607th position is replaced by arginine (Sommer et al. 1991). When the charge of channels is altered, the Ca2+ permeability decreases and the single channel conductivity of the receptor drops. In this mutated state, the channel can no longer be blocked by intracellular polyamines (Verdoorn et al. 1991). In the non-mutant form AMPA receptors’ Ca2+ permeability is determined by the absence of the edited GluA2 subunit (Hollmann et al. 1991; Hume et al. 1991) as previously stated (Wang and Gao 2010). CP-AMPARs are expressed mainly in GABAergic neurons. CP-AMPARs are activated in these interneurons leading to synaptic plasticity through the quick entry of Ca2+ (Lalanne et al. 2016). GluA2 deficient AMPA receptors are rapidly desensitized and blocked by voltage-dependent polyamines in the host cell (Burnashev et al. 1992). The Ca2+ influx through these receptors does not require depolarization and can induce neurotransmitter release without participation of NMDAR and voltage-dependent calcium channels (Isaac et al. 2007; Maiorov et al. 2021).

CP-AMPARs, most of which are composed of GluA1 homomers, are widely found in synapses during early development. After the 14th postnatal day in rodents, CP-AMPARs rapidly decrease in the synapses of most neurons and are almost undetectable in most synapses on excitatory pyramidal neurons in the mature brain (Postnikova et al. 2018). Nevertheless, they are commonly found in inhibitory neurons. In the adult brain, AMPARs which do not contain the GluA2 subunit are mainly localized in the postsynaptic membrane of inhibitory neurons. The expression of CP-AMPARs persists in the synapses of certain GABAergic neurons, including parvalbumin- and somatostatin-positive neurons, as well as in hearing centers throughout life (Pelkey et al. 2015). Nevertheless, complete inhibitory GABAergic synaptic transmission inherent in the mature CNS is formed by the 30th day of postnatal development (P30) (Peerboom and Wierenga 2021).

In addition, an increased expression of CP-AMPARs has been observed among those with elevated drug consumption, and memory disorders (Shepherd 2012). Neuronal networks in the brain are permanently affected by excessive drug consumption, which can cause rapid changes even with a single dose (Caffino et al. 2021). Cocaine-induced plasticity has been attributed to the transport of AMPARs (Luscher and Malenka 2011). During periods of abstinence from cocaine exposure in the brain of the animals, there is a decrease in the GluA2 level and the ADAR2 enzyme responsible for its editing (Wang et al. 2014). Such data suggests that CP-AMPARs activation could potentially stimulate cocaine addiction or contribute to cocaine craving/recurrence among addicts. While the induction protocols that normally induced long-term potentiation (LTP) in DA neurons were successful, they failed to induce LTP in cocaine-treated animals and instead reversed the rules of synaptic plasticity (Mameli et al. 2009). Transmission potentiation is typically induced by depolarization when NMDARs are unblocked, but the currents produced by cocaine injection are reduced, which prevents LTP induction (Huang et al. 2007). Thus, CP-AMPARs of GABAergic neurons are involved in such important processes as plasticity, early development and drug addictions, which are largely related to the transport of AMRARs.

Effect of CP-AMPARs on synaptic plasticity and regulation of receptors number in synapses

The function of the brain is largely dependent on the nature of synaptic interactions among its neurons. Synaptic plasticity is a term used to describe the phenomenon of changes in the strength and duration of the existent interactions between neurons in response to changes related to learning and memory, environmental influences and metabolic processes of the body, brain damage, all of which result in the development of new neuronal interactions (Liu et al. 2003). Synaptic plasticity encompasses the biological process that enables the development of learning and memory to occur through changes in the relations between synapses (Caroni et al. 2012). Synaptic plasticity is a complex process involving various synaptic ion channels and receptors. LTP in hippocampal CA1 synapses is classically triggered by activating of NMDA receptors and CP-AMPARs have also been shown to be involved in the plasticity of synaptic transmission (Sanderson et al. 2018; Dolgacheva et al. 2020). Excitatory neurons tend to only display CP-AMPARs in the case of development (young animals) or after an increase in neuronal activity leading to significant plasticity (Isaac et al. 2007; Liu and Zukin 2007). An increase in synaptic strength of LTP in this case is regulated by the expression of CP-AMPARs containing GluA1, but lacking GluA2 subunits. Many studies have shown that CP-AMPARs modulators potentiate plasticity, improve memory and learning, and are implicated in the genesis of neurodegenerative diseases such as ischemia, stroke and seizures (Azarnia Tehran et al. 2022; Dasgupta and Sikdar 2015; Purkey et al. 2018). CP-AMPARs have been shown to exhibit a stronger effect on plasticity than NMDARs due to their ability to increase intracellular Ca2+ concentration in a voltage-independent manner (Chater and Goda 2014; Lippman-Bell et al. 2016). The main mechanism of LTP induction in the hippocampus is thought to result from changes in CP-AMPARs content in synapses which causes changes in their activity (Park et al. 2018). The number of receptors in synapses is typically regulated by endocytosis, exocytosis, and endosomal sorting (Choquet and Triller 2003). When synaptic transmission efficiency is reduced in long-term depression (LTD), the number of AMPARs at the synapse is reduced due to increased transport of AMPARs into lysosomes resulting in their subsequent degradation, whereas in LTP there is a net increase in the delivery of AMPARs to synapses (van der Sluijs and Hoogenraad 2011). It has been shown that to regulate synaptic strength during homeostatic plasticity and in epilepsy, Ca2+-permeable homomeric GluA1 receptors can be recruited to hippocampal synapses from extrasynaptic and/or intracellular stores (Purkey and Dell'Acqua 2020). It is thought that during hyperexcitation and learning, CP-AMPARs are transported into synapses, modifying synaptic plasticity towards the formation of neuronal connections. In support of this concept, it has been shown that epileptic activity leads to rapid recruitment of CP-AMPARs into the synapses of cortical and hippocampal glutamatergic neurons, which normally do not express those (Szczurowska et al. 2016).

Many studies have reported strong correlations in the emergence of new types of synapses with the induction of certain forms of synaptic plasticity, including LTP, LTD, or after certain behavioral manipulations induced by fear or cocaine relapse and withdrawal syndrome (Soares et al. 2013; Sanderson et al. 2018). Movement and incorporation of CP-AMPARs into the synaptic regions is regulated by phosphorylation of the GluA1 subunit by protein kinases CaMKII and PKA and by dephosphorylation by the phosphatase PP2B (Wang et al. 2020). Intracellular transport of GluA1 requires binding to SAP97, and exocytosis of these subunits requires its binding to scaffolding protein 4.1N (Bonnet et al. 2023). These findings provide evidence that calcium-impermeable GluA2 subunits are involved in LTD expression, whereas CP-AMPAR GluA1 subunits are involved in LTP expression and other forms of synaptic plasticity.

CaMKII and PKC can phosphorylate the GluA1 AMPAR subunit at position S831, increasing the conductance of channels specifically formed by GluA1 homomers (Derkach et al. 1999), whereas PKA-dependent phosphorylation of GluA1 at S845, increases both the conductivity and the probability of opening of a channel (Banke et al. 2000). Knock-in mice expressing GluA1 or GluA2 subunits demonstrated that GluA1 phosphorylation by CaMKII or PKA is required for full expression of hippocampal LTP (Lee et al. 2010), whereas, PKA-dependent GluA1 site dephosphorylation is required for LTD (Man 2011).

Kainate receptors, subunit composition, editing, and Ca2+ permeability

Tetrameric kainate receptors (KARs) consist of two distinct families of subunits: low-affinity agonist subunits (GluK1-GluK3) and high-affinity agonist subunits (GluK4-GluK5) (Graham et al. 2009). Studies using recombinant systems show that GluK1-3 group subunits can form ion channels in both homomeric and heteromeric forms, whereas GluK4 and GluK5 subunits can form heteromeric functional ion channels only with low-affinity subunits (Burnashev et al. 1992).

Kainate receptor channels are located pre-, post- and/or extrasynaptically, where they can induce either neurotransmitter release or postsynaptic depolarization, thereby regulating neuronal excitation. A certain subtype of KAR is permeable to calcium and is specified as CP-KARs (Lerma 2003; Sun et al. 2009). The change in channel permeability is the result of post-translational modifications (Evans et al. 2019). Most KARs contain GluK1 and GluK2 subunits, whose pre-mRNA can undergo editing by the adenosine deaminase enzyme ADAR2, followed by replacement of a glutamine residue with an arginine residue in these subunits (Q/R editing) (Nishikura 2016). Q/R editing in the GluK2 pore-lining region affects both Ca2+-permeability and other biophysical properties of KARs (Gurung et al. 2018). GluK2(R)-containing KARs are impermeable to Ca2+, having a channel conductance of less than 1% compared with unedited and those containing GluK2(Q) (Swanson et al. 1996). The ratio of calcium-permeable to calcium-impermeable receptors changes greatly in the postnatal period, apparently due to ADAR2 content. The level of ADAR2 is very low during embryogenesis, but increases in the first postnatal week (Behm et al. 2017). In the mature brain, ~ 80% of GluK2 subunits, ~ 40% of GluK1, and ~ 99% of GluA2 subunits are edited (Filippini et al. 2016; Paschen et al. 1997).

KARs play a more complicated role in synaptic plasticity than AMPARs, due to difference in their localization in post- and presynaptic membranes. Similar to CP-AMPARs, in the adult brain CP-KAR receptors are mainly localized in GABAergic neurons (Contractor et al. 2001). However, in contrast to CP-AMPARs, CP-KAR receptors are located mainly in the presynapse region of GABAergic neurons (Kieval et al. 2001). CP-KAR receptors, due to their properties (high affinity to glutamate, increased excitation, absence of desensitization, presence of the calcium-binding protein parvalbumin), respond more quickly to activation by increasing Ca2+ concentration in the cytosol, which leads to advanced GABA release and suppression of glutamatergic neurons activity (Zinchenko et al. 2021).

Recent works have shown that GABAergic neurons expressing CP-KARs are innervated by GABAergic neurons expressing CP-AMPARs. Activation of CP-AMPARs simultaneously inhibits the activity of GABAergic neurons expressing CP-KARs and thus causes disinhibition of glutamatergic neurons (Fig. 1). This also explains the fact that selective blockers of CP-AMPARs (GABAergic neurons) have a neuroprotective effect, preventing the death of neurons during ischemia. Some separate studies show that KARs can induce a new form of LTP even in adult rats and GluK2 editing plays an important role in this process (Contractor et al. 2011; Jane et al. 2009). Unlike conventional NMDAR-dependent post-LTP, the transduction of pre-LTP involves activation of GluK1-containing KARs, protein kinase A (Nicoll and Schmitz 2005), and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (Chevaleyre and Castillo 2002).

Fig. 1.

Fig. 1

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GABAergic neurons expressing CP-AMPARs are involved in the disinhibition of glutamatergic neurons due to suppression of GABAergic neurons expressing CP-KARs. The activation of GABAergic neurons expressing CP-AMPARs (upper neuron) initiates Ca2+ rise and GABA release. The GABA interacts with GABA(A) and GABA(B) receptors in pre- and postsynapse of GABAergic neurons expressing CP-KARs (second neuron). In the presynapse, the metabotropic GABA(B) receptor is colocalized with the Ca2+-channel, and the βγ subunits of Gi protein (activated by this receptor) inhibit the channel. In the postsynapse, the receptor is colocalized with the K+-channel, and the βγ-subunit of the Gi protein opens this channel, initiating hyperpolarization and suppressing GABA release. GABA concentration decrease removes inhibition from the glutamatergic neuron (third neuron). The selective antagonist of CP-AMPAR, NASPM, inversely causes inhibition of glutamatergic neuron (Zinchenko et al. 2021)

Recently, neurons containing CP-KARs and CP-AMPARs were visualized in rat hippocampal cells culture (Zinchenko et al. 2020). Using selective agonists and antagonists, domoic acid as an activator of both receptor types, ATPA and LY293558 as selective CP-KARs agonists and the selective CP-AMPARs blocker 1-Naphthyl acetyl spermine (NASPM), the authors showed that not only brain cognitive functions such as perception, signal processing and analysis, memory, storage and information exchange are controlled by GABAergic neurons expressing CP-KARs and CP-AMPARs, but the receptors are also involved in switching to a state of hyperexcitation. Such a significant role of CP-AMPARs and CP-KARs GABAergic neurons in modulating synaptic transmission is determined not only by the calcium permeability of the receptors, but also by their ability to respond to excitation earlier and faster than other glutamatergic neurons, which leads to suppression of hyperexcitation in the network by advanced GABA release (Zinchenko et al. 2021).

Conclusion

Thus, glutamate CP-KARs and CP-AMPARs play a key role in the regulation of hyperexcitation and synaptic plasticity of GABAergic neurons. These effects are largely due to high affinity for receptor agonists, increased neuronal excitation, and impaired GABA(A) receptor-dependent inhibition in GABAergic neurons containing CP-KARs and CP-AMPARs (Gaidin et al. 2023).

Author contribution

V.Z. conceptualized and outlined the review. L.D. wrote the first draft of the manuscript. S.T. review & editing and all three authors finalized the manuscript.

Funding

This research has been funded by the Science Committee of the Ministry of Science and Higher Education of the Republic of Kazakhstan (Grant No. AP19680470 “Involvement of phosphoinositol diphosphate (PIP2) and Kv7 potassium channels in the regulation of hyperexcitation in an epileptic model”).

Data Availability

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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