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. Author manuscript; available in PMC: 2010 Aug 1.
Published in final edited form as: J Neurochem. 2009 Jun 15;110(4):1150. doi: 10.1111/j.1471-4159.2009.06223.x

Circadian regulation of ion channels and their functions

Gladys Y-P Ko 1, Liheng Shi 1, Michael L Ko 1
PMCID: PMC2819050  NIHMSID: NIHMS169123  PMID: 19549279

Abstract

Ion channels are the gatekeepers to neuronal excitability. Retinal neurons of vertebrates and invertebrates, neurons of the suprachiasmatic nucleus (SCN) of vertebrates, and pinealocytes of non-mammalian vertebrates display daily rhythms in their activities. The interlocking transcription–translation feedback loops with specific post-translational modulations within individual cells form the molecular clock, the basic mechanism that maintains the autonomic ~24-h rhythm. The molecular clock regulates downstream output signaling pathways that further modulate activities of various ion channels. Ultimately, it is the circadian regulation of ion channel properties that govern excitability and behavior output of these neurons. In this review, we focus on the recent development of research in circadian neurobiology mainly from 1980 forward. We will emphasize the circadian regulation of various ion channels, including cGMP-gated cation channels, various voltage-gated calcium and potassium channels, Na+/K+-ATPase, and a long-opening cation channel. The cellular mechanisms underlying the circadian regulation of these ion channels and their functions in various tissues and organisms will also be discussed. Despite the magnitude of chronobiological studies in recent years, the circadian regulation of ion channels still remains largely unexplored. Through more investigation and understanding of the circadian regulation of ion channels, the future development of therapeutic strategies for the treatment of sleep disorders, cardiovascular diseases, and other illnesses linked to circadian misalignment will benefit.

Keywords: circadian, ion channels, pineal gland, retina, signaling, suprachiasmatic nucleus

General introduction of the circadian oscillators and their functions

Circadian oscillators are biological clocks that exist in almost all living organisms from bacteria to humans, with persistent rhythmic periods close to 24 h (circa dian) even in the absence of external timing cues. The circadian oscillators coordinate rhythmic changes in biochemistry, physiology, and behavior of living organisms so that they can be synchronized with the 24-h oscillations of the external environment. The molecular nature of circadian oscillators, the ‘molecular clock,’ varies from species to species. A generalized model for the generation of mammalian circadian rhythms involves two interlocking transcription–translation feedback loops (Fig. 1). CLOCK (circadian locomotor output cycles kaput) and BMAL (brain and muscle, ARNT-like) 1 (Mop3) are two basic helix-loop-helix-PAS (Period-Arnt-Single-minded) transcription factors. CLOCK and BMAL1 form heterodimers and activate the transcription of downstream genes containing E-box cis regulatory enhancer sequences in their promoter regions, including the Period (Per1/Per2/Per3) and Cryptochrome (Cry1/Cry2) genes. While Bmal1 is maximally expressed during the middle of the night, the transcript levels of Pers and Crys reach their peaks during mid to late day, which are anti-phase to Bmal1 expression. The PERs, CRYs, and other proteins form heteromultimeric complexes that translocate into the nucleus and directly abrogate the transcriptional activity of the CLOCK–BMAL1 complex, thereby lowering Per and Cry mRNA levels. Thus, PERs, CRYs, and associated proteins regulate their own transcription through the inhibition of transcriptional activity of the CLOCK–BMAL1 heterodimers. Two members (Iδ and Iε) of the casein kinase family are involved in post-translational phosphorylation of PERs and ultimately contribute to their degradation. Another feedback loop includes the retinoic acid-related orphan nuclear receptor, REV–ERBα (reverse orientation c-erbA-1 gene alpha; an orphan nuclear receptor), which also is one of the downstream genes activated by CLOCK–BMAL1 heterodimers. The REV–ERBα protein represses Bmal1 gene expression through binding the retinoic acid-related orphan receptor response elements in Bmal1’s promoter. Therefore, BMAL1 attenuates its own transcription by transcriptional activation of REV–ERBα. Together, these positive and negative feedback loops are the major components of the mammalian molecular clock (Lowrey and Takahashi 2004). They play critical roles in establishing the circadian rhythm (for more detail on the molecular nature of circadian oscillators across species, please see the review by Bell-Pedersen et al. 2005). More recently, the role of micro-RNAs serving as post-transcriptional regulators, as well as other post-translational modulations, including phosphorylation/dephosphorylation, acetylation, and ubiquitination have been observed to play important parts in the molecular mechanisms underlying the circadian clock (Kim et al. 2003; Cheng et al. 2007; Hirayama et al. 2007; Jakubcakova et al. 2007). Collectively, these components comprise the core oscillator or the circadian oscillator (Dunlap 1999; Shearman et al. 2000; Glossop and Hardin 2002; Cyran et al. 2003).

Fig. 1.

Fig. 1

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This diagram illustrates a general model of the mammalian circadian oscillator in the SCN. The molecular clock is composed of interlocking transcription–translation feedback loops. CLOCK and BMAL1 (Mop3) are two basic helix-loop-helix-PAS (Period-Arnt-Single-minded) transcription factors, and Bmal1 is maximally expressed during the middle of the night. CLOCK and BMAL1 form heterodimers and activate the transcription of downstream genes containing E-box cis regulatory enhancer sequences in their promoter regions, including the Period (Per1/Per2/Per3) and Cryptochrome (Cry1/Cry2) genes. The transcript levels of both Pers and Crys reach their peak during mid to late day, which are anti-phase to Bmal1 expression. Two members of the casein kinase Iδ and Iε family are involved in post-translational phosphorylation of PERs and ultimately contribute to their degradation. The PERs, CRYs, and other proteins form heteromultimeric complexes that translocate into the nucleus and directly abrogate the transcriptional activity of the CLOCK–BMAL1 complex, thereby lowering Per and Cry mRNA levels. Thus, PERs, CRYs, and associated proteins regulate their own transcription through the inhibition of transcriptional activity of the CLOCK–BMAL1 heterodimers. Another feedback loop includes the retinoic acid-related orphan nuclear receptor, REV–ERBα, which also is one of the downstream genes activated by CLOCK–BMAL1 heterodimers. The REV–ERBα protein represses Bmal1 gene expression through binding the retinoic acid-related orphan receptor response elements (ROREs) in Bmal1’s promoter. Therefore, BMAL1 attenuates its own transcription by transcriptional activation of REV–ERBα. Collectively, these positive and negative feedback loops are the major components of the mammalian molecular clock. They play critical roles in establishing the circadian rhythm (figure is modified from Lowrey and Takahashi 2004).

The circadian oscillators in the mammalian suprachiasmatic nucleus

In higher vertebrates, circadian oscillators exist in the brain as well as in other organs or tissues (Bell-Pedersen et al. 2005). The ‘master clock’ that coordinates the activities of other oscillators is located in the suprachiasmatic nuclei (SCN) of the hypothalamus, while circadian oscillators existing in other brain areas or tissues are called peripheral clocks (or slave clocks) and are under the influence of the SCN (Balsalobre et al. 2000; Cheng et al. 2002). The SCN receives light information from the retina through the retinohypothalamic tract (Nauta and Haymaker 1969; Moore and Lenn 1972), which allows for the setting of SCN circadian oscillators to external light cues (Johnson et al. 1988). Surgical ablation of the SCN in mammals causes animals to become arrhythmic in locomotor activities, endocrine output, and other biochemical and physiological processes (Turek 1985). Transplantation of SCN tissue to SCN-lesioned animals restores circadian rhythms (Ralph et al. 1990). Furthermore, individual SCN neurons can generate self-sustained molecular and physiological oscillations, including circadian rhythmicity of action potential firing rates (Green and Gillette 1982; Shibata and Moore 1988; Welsh et al. 1995; Quintero et al. 2003). In addition, the increase in spontaneous firing during the daytime in mammalian SCN neurons is associated with autonomic circadian regulation of ion channel activities (discussed in detail later; Meredith et al. 2006; Wang and Huang 2006). Hence, the SCN is the major pacemaker responsible for setting the phase and period of the biological rhythms in higher vertebrates (Bell-Pedersen et al. 2005).

The circadian oscillators in the retina

As a unique photosensitive tissue, the retina possesses its own independent circadian oscillators, which allow the retina to anticipate the daily cycling light (Green and Besharse 2004). In addition, communication between the retina and SCN through the retinohypothalamic tract affects the circadian phase of the SCN (Berson et al. 2002). Visual systems have to detect images despite large daily changes in ambient illumination between day and night, and intrinsic circadian oscillators in the retina provide such a mechanism for visual systems to initiate more sustained adaptive changes throughout the course of the day (Cahill and Besharse 1995; Green and Besharse 2004). The retina is heterogeneous with multiple cell types organized in several layers. Early studies of circadian regulation in Xenopus and chicken retinas indicated that retinal circadian clocks are mainly located in the photoreceptors (Korenbrot and Fernald 1989; Cahill and Besharse 1993; Pierce et al. 1993; Green et al. 1995a). Later research revealed that there are multiple oscillators present in other retinal cells including bipolar, ganglion, amacrine, and horizontal cells in a species-dependent manner (photo-receptors: Xenopus-Constance et al. 2005; fish-Halstenberg et al. 2005; Li et al. 2005; Menger et al. 2005; Yu et al. 2007; avian-Bernard et al. 1997; Chong et al. 1998; Ivanova and Iuvone 2003a; Ko et al. 2001; Manglapus et al. 1998; rats-Tosini et al. 2008; bipolar cells: fish-Hull et al. 2006; mice-Ruan et al. 2006; ganglion cells: mice-Garbarino-Pico et al. 2004a,b; Ruan et al. 2006; amacrine cells: mice-Dorenbos et al. 2007; horizontal cells: mice-Ruan et al. 2006; fish-Wang and Mangel 1996). The overall circadian regulation of the retina relies on the synaptic circuitry and feedback modulation among different retinal oscillators, so that the retina is able to anticipate and adapt to sustained daily illumination changes as well as acute light/dark adaptation (for more detail on the circadian regulation of the retina, please see the review by Wiechmann and Summers 2008).

The endogenous circadian oscillators in photoreceptors are able to function independently in the absence of other retinal inputs (Cahill and Besharse 1993; Thomas et al. 1993; Ko et al. 2001). These photoreceptor oscillators lead to morphological, physiological, biochemical, and molecular changes that ultimately regulate photoreceptor function and physiology in a circadian fashion. For example, in vertebrate rod and cone photoreceptors, outer segment phagocytosis, shedding, and renewal are continuous processes, but their rates are under circadian control. The circadian phase of the rhythmic shedding and renewal in both cones and rods is highly species dependent (Anderson et al. 1978, 1980; LaVail 1980; Besharse and Dunis 1983; Fisher et al. 1983; Reme et al. 1986; Bobu et al. 2006), while the photosensitive membrane undergoes daily turnover in the lateral eye of Limulus (Runyon et al. 2004). In some teleosts and anaurans, the inner segments of rod and cone photoreceptors undergo contraction and elongation (i.e. retinomotor movement) in circadian cycles as well as in response to changes in ambient illumination (Nagle and Burnside 1984; Pierce and Besharse 1985, 1988; Wagner et al. 1993; Burnside 2001; Menger et al. 2005). While cones remain in a contracted state during the day, rods contract at night. Photoreceptors form specialized ribbon synapses with secondary neurons like horizontal or bipolar cells. The number and ultrastructure of synaptic ribbons in both photoreceptors and bipolar cells undertake changes in relation to the time of day and light intensity (Vollrath et al. 1989; Vollrath and Spiwoks-Becker 1996; Adly et al. 1999; Allwardt et al. 2001; Spiwoks-Becker et al. 2004; Hull et al. 2006). In avian, amphibian, reptile, and other lower vertebrate species, the transcription of arylalkylamine N-acetyltransferase (AANAT), the melatonin synthesis enzyme, is under circadian control (Bernard et al. 1997; Iuvone et al. 1997, 1999; Ivanova and Iuvone 2003b), which leads to higher synthesis and secretion of melatonin from photoreceptors at night, while its synthesis is inhibited by light (Cahill and Besharse 1993; Bernard et al. 1997; Ivanova and Iuvone 2003b). Also, while the synthesis and release of dopamine from retinal amacrine cells show light-driven and circadian fluctuations (Iuvone et al. 1978; Wirz-Justice et al. 1984; Pierce and Besharse 1985; Manglapus et al. 1999; Ribelayga et al. 2004; Witkovsky et al. 2004), the circadian nature of dopamine is dependent on the melatonin rhythm (Doyle et al. 2002; Miranda-Anaya et al. 2002; Ribelayga et al. 2004). In addition to the circadian oscillator genes, several genes majorly expressed in photoreceptors (e.g. opsin) are also under circadian regulation (Korenbrot and Fernald 1989; Pierce et al. 1993; Bailey et al. 2004; Liang et al. 2004). The circadian oscillators also regulate ion channel and kinase activities in the photo-receptors that ultimately contribute to the circadian regulation of photoreceptor physiology and function (Green et al. 1995a,b; Hasegawa and Cahill 1999a, 2004; Ko et al. 2001, 2003, 2004, 2007; Chae et al. 2007; Chen et al. 2007).

The circadian rhythms in the pineal gland

The major function of the pineal gland is the synthesis and release of melatonin, a neurohormone, which is elevated at night and circulated throughout the body serving as a signal of time to integrate physiological functions with environmental lighting on a daily and seasonal basis (Bailey et al. 2009; for more recent reviews, please see Klein 2006; Macchi and Bruce 2004). In lower vertebrates, pinealocytes possess a photosensitive and autonomic circadian rhythm in melatonin secretion that persists in dissociated cell cultures (Robertson and Takahashi 1988a,b; Zatz and Mullen 1988a; Zatz et al. 1988). In fact, avian pinealocytes resemble retinal cone photoreceptors as they both have oil droplets, utilize opsin, arrestin, transducin, and cGMP-gated cation channels (CNGCs) for phototransduction, and display hyperpolarizing responses to brief pulses of light (Pu and Dowling 1981; Tamotsu and Morita 1986; Dryer and Henderson 1991). Interestingly, mammalian pinealocytes are not sensitive to light, and the circadian oscillation in pineal melatonin production in this case is under SCN control through a polysynaptic pathway that involves both central and peripheral neuronal structures (review in Maronde and Stehle 2007). Even though the mammalian pineal gland serves as a peripheral oscillator driven by the SCN, the machinery for the production of melatonin, including the expression of key enzymes AANAT and hydroxyindole-O-methyltransferase that synthesize melatonin, is under circadian control (Klein 2006; Maronde and Stehle 2007). Over 600 genes that are important for immunity, cell cycle and death, intracellular signaling molecules, transcription factors, and circadian rhythmicity are also under circadian regulation in the mammalian pineal gland (Bailey et al. 2009). However, the molecular mechanism underlying melatonin secretion from pinealocytes is still not well understood, and the circadian regulation of cell excitability or ion channel activity have only been documented in non-mammalian pinealocytes.

The circadian oscillators in other neuronal tissues

Circadian oscillators in other brain areas also impact the regulation of a variety of functions. For example, clock genes and other components of the molecular clock display circadian rhythmicity in the hippocampus (Stephan and Kovacevic 1978; Eckel-Mahan et al. 2008). Lesions of the SCN, clock gene knockouts, or light-induced arrhythmic animals fail to perform hippocampal-dependent learning tasks (Ruby et al. 2008). Interestingly, in Aplysia, circadian oscillators regulate complex learning and memory formation and long-term sensitization (Lyons et al. 2005). This circadian-regulated memory formation in Aplysia is possibly mediated through a glutamate transporter (Collado et al. 2007). Furthermore, circadian oscillators in Drosophila melanogaster modulate the formation of short-term associative memory (Lyons and Roman 2009). However, there are peripheral oscillators that can function independently without input from the ‘master clock,’ and the olfactory system is one of them. The first evidence of an independent olfactory oscillator was found from the Drosophila antennae (Krishnan et al. 1999). The master clocks that control locomotor activity rhythms and sleep–wake cycles in Drosophila are located in the lateral neurons (Bell-Pedersen et al. 2005). In the Drosophila antennae, odorant-evoked neuronal responses are significantly higher at night (Krishnan et al. 1999, 2001, 2008), and this observation is correlated with an increase in nocturnal sex drive (Fujii et al. 2007). Targeted ablation of lateral neurons by using apoptosis-promoting factors demonstrates that the antennae neurons are necessary and sufficient for the circadian rhythm in the Drosophila olfactory system (Tanoue et al. 2004). In mammals, odor-induced c-Fos expression in the olfactory bulbs and piriform cortex is also under circadian control (Granados-Fuentes et al. 2006). Electrolytic lesions of the SCN abolish circadian locomotor rhythms but not odor-induced c-Fos rhythms in both olfactory bulbs and piriform cortex. However, surgical removal of both olfactory bulbs shortens the free-running period of locomotor rhythms and alters the circadian phases, which indicates that olfactory oscillators in mammals may interact with the SCN to coordinate other daily behaviors (Granados-Fuentes et al. 2006).

Circadian regulation of ion channels

Ion channels are macromolecular pores that allow charged ions to move across the cell membrane and contribute to the excitability of neurons and muscles (Hille 2001). Despite what research has accomplished on the properties, modulation, and physiological functions of ion channels in various neurons and glial cells, the circadian regulation of ion channels and the resulting physiological effects have yet to be fully explored. Thus far, circadian changes in gating properties and the corresponding impacts on physiological functions have been studied in CNGCs, voltage-gated calcium channels (VGCCs), and various potassium channels in the retina or SCN. These and other ion channels have been reported to be under circadian regulation and will be discussed in detail below. As ion channels are the gatekeepers of neuronal activity, their regulation by circadian oscillators could serve as the final posts of oscillator neurons to regulate downstream targets, synchronize local oscillators, and further regulate physiological states and behaviors. On the other hand, ion influx/efflux can activate or inactivate various cellular signaling pathways that might cause changes in circadian gene expression, which in turn can lead to shifts in circadian phases. Therefore, ion channels can serve in circadian input and/or output pathways. Furthermore, the circadian regulation of ion channels can enhance the stability of circadian oscillators, which demonstrates a model that Roenneberg and Merrow (1999) presented where the elements that lead to entrainment of the core oscillators (e.g. the ion channels) can themselves be regulated by the oscillators. One feature of this model is that it contains additional feedback loops that can markedly enhance the stability of the overall oscillator system at the cellular level and possibly at the network level (e.g. the retinal oscillators). Table 1 is a summary of ion channels that are under circadian control and their functions related with circadian rhythm in various tissues and organisms.

Table 1.

List of ion channels that are under circadian control in various neuronal tissues studied in different species, as well as their functions related with circadian rhythms

Ion channel Cell type Function Organisms studied
cGMP-gated ion channels Retinal cone photoreceptors Circadian sensitivity to light Chicken
L-type voltage-gated calcium channels Retinal cone photoreceptors Circadian regulation of melatonin and retinoschisin Chicken
Retinal bipolar cells Circadian regulation of synaptic ribbons Fish
Suprachiasmatic nucleus Circadian regulation of intracellular calcium levels Rat, Mouse
Circadian regulation of spontaneous firing rates of SCN neurons
T-type voltage-gated calcium channels Thalamus, suprachiasmatic nucleus, cerebellum Regulation of sleep–wake cycle, circadian phase-shifting Rat, Mouse
Voltage-gated potassium channels Retinal pacemaker neurons Circadian regulation of the compound action potential firing frequency Aplysia
Basal retinal neurons Circadian regulation of membrane conductance and membrane potential; circadian regulation of optic nerve impulses Mollusk Bulla gouldiana
Voltage-gated potassium channels: Shaker, Shaw Neurons and neurosecretory cells Sleep periods, rhythmic locomotor behavior, resting membrane potential Drosophila
Voltage-gated potassium channels: Kv3.1, Kv3.2 Suprachiasmatic nucleus Circadian regulation of spontaneous firing rate of SCN neurons Mouse
Calcium-activated potassium channels Photoreceptors, neurons in the head, and neurosecretory cells Circadian rhythm of locomotor activity Drosophila
Suprachiasmatic nucleus Circadian regulation of spontaneous firing rates of SCN neurons; Circadian locomotor activity and physiological rhythms Rat, Mouse
Na+/K+-ATPase Suprachiasmatic nucleus Circadian regulation of spontaneous firing rates of SCN neurons Rat
Long-opening time cation channel (ILOT) Pineal gland Potential synchronization of pineal oscillators in non-mammalian species Chicken
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Circadian regulation of cGMP-gated cation channels

Cyclic GMP-gated cation channels are non-selective cation channels that belong to a family of cyclic nucleotide-gated channels (Kaupp and Seifert 2002). In general, cyclic nucleotide-gated channels are heterotetrameric complexes consisting of two or three different types of subunits (α, β, and γ), with important channel properties determined by the subunit composition. Activation of these channels is through direct binding of cyclic nucleotides onto the channel proteins (Kaupp and Seifert 2002). The CNGCs of rods and cones are structurally similar but have distinct α- and β-subunits (Zheng et al. 2002; Zhong et al. 2002; Bradley et al. 2005). Rods contain CNGCα1 subunits that are more sensitive to calcium-induced inhibitions, while cones contain CNGCα3 subunits that are not as sensitive to calcium (Miller and Korenbrot 1994; Korenbrot 1995; Kaupp and Seifert 2002; Krajewski et al. 2003). In the vertebrate retina, photo-transduction is mediated by a G protein-coupled cascade that results in changes in the gating of CNGCs in the outer segments of rods and cones (Zagotta and Siegelbaum 1996; Matulef and Zagotta 2003). Light initiates a fall in intracellular cGMP as the end-point of a G protein-mediated phototransduction cascade, resulting in closure of CNGCs, reduced cation influx, and membrane hyperpolarization (Fig. 2a). In the dark, the intracellular cGMP concentration is relatively high, which causes tonic activation of these channels and a steady transmembrane influx of sodium (Na+) and calcium (Ca2+) ions (Yau and Baylor 1989; Pugh and Lamb 2000). Therefore, CNGCs carry the photoreceptor ‘dark current’ and serve essential roles in the light-dependent changes in photoreceptor membrane potential and subsequent neural processing (Fig. 2b).

Fig. 2.

Fig. 2

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(a) Figure illustrate a simplified model of phototransduction in photoreceptors. In the light, after opsins/rhodopsins (R) receive photons, activated opsins/rhodopsins (R′) bind to the G protein transducin (GTαβγ). The α subunit of transducin (G′Tα) separates from the βγ subunit complex and activates phosphodiesterase. The activated phosphodiesterase (PDE′) degrades the phosphodiester bond of cGMP (cG) changing it to GMP. With less cGMP available for cGMP-gated cation channels (CNGCs), these channels close and hyperpolarize the photoreceptors. (b) In the dark (or at night), there is more intracellular cGMP available for CNGCs. After cGMP binds to the CNGCs, the channels open and allow an influx of sodium (Na+) and calcium (Ca2+) causing depolarization of the photoreceptors. Depolarization of the photoreceptor plasma membrane in turn allows calcium to enter the cells through L-type voltage-gated calcium channels (L-VGCCs). The Ca2+ influx further activates the synthesis and secretion of melatonin, and it also correlates with the arrangement of synaptic vesicles at ribbon synapses, which allows for more efficient neurotransmitter release.

Circadian regulation of cGMP-gated ion channels in retinal photoreceptors

In chicken cone photoreceptors, the apparent affinity of CNGCs for their activating ligand is under circadian regulation (Ko et al. 2001, 2003, 2004; Chae et al. 2007). There is roughly a twofold change in the apparent affinity of CNGCs for cGMP throughout the course of a day, with the affinity substantially higher at night than during the day even in constant darkness conditions after light/dark entrainment. Such changes in channel affinities can be expected to occur at the lower range of cGMP concentrations (≤ 7 μM in the dark) that are within the photoreceptor physiological range (Cobbs and Pugh 1985; Cobbs et al. 1985; Ko et al. 2001). Other biophysical features of CNGC gating, such as unitary conductance, Hill coefficient, density of channels in the plasma membrane, and maximum current amplitudes do not vary as a function of the time of day (Cobbs and Pugh 1985; Cobbs et al. 1985; Ko et al. 2001).

The gating properties of photoreceptor CNGCs can be modulated by multiple processes, including direct phosphorylation or dephosphorylation of the channel subunits and the binding of Ca2+/calmodulin or related molecules (Hsu and Molday 1993; Gordon et al. 1995; Bauer 1996; Kosolapov and Bobkov 1996). Dephosphorylation of CNGC serine/threonine (Gordon et al. 1992) or tyrosine residues (Molokanova et al. 1997, 1999a,b) causes an increase in the apparent affinity of CNGCs for their activating ligand. Binding of Ca2+/calmodulin or phosphorylation of CNGCs causes these channels to shift to a lower affinity state for cGMP (Hsu and Molday 1993; Gordon et al. 1995; Bauer 1996; Kosolapov and Bobkov 1996; Krajewski et al. 2003). The clock regulation of cone CNGCs entails a post-translational modification of the channel molecules. More specifically, it is the circadian rhythmicity of tyrosine phosphorylation that underlies the circadian modulation of cone CNGC affinity to its ligand (Ko et al. 2001, 2004; Chae et al. 2007). Inhibition of tyrosine kinases during the day increases the apparent affinity of CNGCs for cGMP, whereas inhibition of tyrosine phosphatases at night produces the opposite effect (Chae et al. 2007). While the protein expression and phosphorylation of the channel pore-forming CNGCα3 subunits remain constant throughout the day, tyrosine phosphorylation of an auxiliary subunit (probably the β subunit, ~85 kDa) displays a circadian rhythm (Chae et al. 2007). During the daytime, tyrosine phosphorylation on this 85-kDa protein is twice as high as at night. Therefore, the circadian rhythmicity of tyrosine phosphorylation on the 85-kDa auxiliary subunit of cone CNGCs provides one of the final steps in the circadian regulation of CNGCs.

The CNGCs in photoreceptors are essential components of visual phototransduction cascades. As such, it is possible that they also play a role in the light entrainment of the circadian oscillators in photoreceptors. Because the gating of CNGCs is under circadian control in cone photoreceptors, these channels represent a potential example of an entity that is both an input to and an output from the circadian oscillator. Roenneberg and Merrow (1999) have presented models of circadian oscillator systems in which pathways that lead to entrainment of the core oscillators (i.e. the circadian inputs) can themselves be regulated by the oscillators (i.e. they are also components of circadian outputs). One feature of these models is that they contain additional feedback loops that can markedly enhance the stability of the overall oscillator system. Therefore, the circadian regulation of CNGCs in retinal photoreceptors represents an adaptation to enhance the stability of the circadian oscillators in photoreceptors (Ko et al. 2001).

Signaling pathways leading to the circadian regulation of cGMP-gated ion channels

Even though the connection from the molecular oscillator to the regulation of the CNGC affinity rhythm is still not completely understood, the small GTPase Ras, the mitogen-activated protein kinase (MAPK) signaling pathway, and calcium–calmodulin kinase II (CaMKII) are involved as circadian outputs to regulate CNGC rhythms (Ko et al. 2001, 2004). The activities of Ras and MAPK are themselves under circadian control and oscillate concurrently with the CNGC affinity rhythm (Ko et al. 2001, 2004). The activity of CaMKII also displays a circadian rhythm, but it runs anti-phase to the MAPK rhythm, and CaMKII is a downstream target of MAPK (Ko et al. 2001). Perturbation of the activities of Ras, MAPK, or CaMKII causes phase-dependent changes in the gating properties of CNGCs. Furthermore, this Ras–MAPK–CaMKII pathway serves as part of a common circadian output pathway that regulates other photoreceptor molecules (Ko et al. 2007, 2008). However, neither MAPK nor CaMKII directly phosphorylate CNGCs in a circadian fashion. It is their downstream targets leading to tyrosine phosphorylation on the auxiliary subunit of CNGCs that ultimately govern the circadian regulation of CNGC gating properties (Fig. 3).

Fig. 3.

Fig. 3

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This model illustrates the circadian rhythm in chicken cone photoreceptors. Light and dark (day and night) signals from the environment enter the photoreceptor through CNGCs, which are essential in phototransduction. The light/dark signals through the ‘circadian input’ pathway entrain the photoreceptor core oscillator that cause the photoreceptor to be synchronized with the environment. From the core oscillator through the ‘circadian output,’ the activities of different molecules, including CNGCs, L-VGCCs, and retinoschisin are under circadian regulation, and the ‘circadian output’ is composed of a series of signaling pathways. Calcium influx through L-VGCCs causes changes in the signaling involved in the ‘circadian input’ pathway that regulates the core oscillator genes and cAMP signaling, and further regulates the gene and protein expression of AANAT and melatonin production (as indicated by the red dotted arrows). The circadian regulation of CNGCs and L-VGCCs in retinal photoreceptors represents an adaptation to enhance the stability of retinal circadian oscillators. It demonstrates a model that Roenneberg and Merrow (1999) presented, in which the elements that lead to entrainment or modulation of the core oscillators (e.g. CNGCs and L-VGCCs) can themselves be regulated by the oscillators. One feature of this model is that it contains additional feedback loops that can markedly enhance the stability of the overall oscillator system at the cellular level (photoreceptors only) and maybe at the retinal network level (the retinal oscillators). Dotted arrows indicate multiple steps currently not known, while the solid arrows represent known signaling. The Ras, Erk, and CaMKII signaling pathway serves as a common circadian output to regulate the circadian rhythms of CNGCs, L-VGCCs, and retinoschisin in photoreceptors. The circadian regulation of CNGCs involves tyrosine phosphorylation on an auxiliary subunit, in which the phosphorylation is high during the day corresponding to when CNGCs have a lower affinity to cGMP. The circadian phase-dependent regulation of CNGCs by dopamine and somatostatin is represented by brown and purple dotted arrows, respectively. The circadian regulation of L-VGCCs involves the regulation of L-VGCCα1 mRNA and protein expression, as well as the plasma membrane insertion and retention of L-VGCCα1. Circadian regulation of AANAT and melatonin production is partially through the circadian rhythm of cAMP production and direct regulation of AANAT mRNA expression by the core oscillator genes. The purple dotted arrow represents the circadian regulation of transcription and translation of L-VGCCα1 subunits. Functional expression of both L-VGCCα1 and retinoschisin are high at night, and there is a bidirectional feedback regulation between them. Blue dotted arrows indicate that the secretion of melatonin and retinoschisin is under the control of L-VGCCs. The green dotted arrow represents the positive feedback regulation of retinoschisin on L-VGCCα1 subunit retention in the plasma membrane. The red dotted arrow represents the circadian input from the calcium influx through the L-VGCCs. AANAT, aryl-alkylamine N-acetyltransferase; Ca2+, calcium ion; CaMKII, calcium–calmodulin kinase II; CNGC, cGMP-gated cation channel (β, the β subunit of CNGC; p, tyrosine phosphorylation on the CNGCβ subunit); DA, dopamine; D2: dopamine D2 receptor; G, G protein; L-VGCCα1, L-type voltage-gated calcium channel α1 subunit; SS, somatostatin; SSR, somatostatin receptor.

The expression and activation of adenylate cyclase in the retina is also under circadian control (Chaurasia et al. 2006), and the cAMP content in retinal photoreceptors is maximal at night (Ivanova and Iuvone 2003a,b; Chaurasia et al. 2006). In avian retinas, this cAMP rhythm not only drives the rhythm of melatonin synthesis and secretion (Ivanova and Iuvone 2003a,b; Chaurasia et al. 2006), it also serves as part of the circadian output and leads to MAPK activation and modulation of the CNGC affinity rhythm. Aside from serving as a circadian output to regulate ion channels, cAMP can stimulate retinomotor movements (Besharse et al. 1982; Burnside et al. 1982; Burnside and Ackland 1984; Burnside 2001). In Xenopus retina, cAMP signaling resets circadian oscillators within photoreceptors (Hasegawa and Cahill 1998, 1999b). Hence, the second messenger, cAMP, may well serve as part of both input and output pathways in photoreceptors.

Circadian phase-dependent modulation of cone cGMP-gated ion channels by dopamine

While circadian rhythms can occur in retinal photoreceptors cultured in the absence of other functional cell types (Cahill and Besharse 1993; Ko et al. 2001), multiple cell types contribute to the overall circadian control of the intact retina. In avian retina, melatonin inhibits the release of dopamine from a subpopulation of amacrine cells (Nowak et al. 1992). Consequently, retinal melatonin and dopamine have anti-phasic circadian cycles (Adachi et al. 1998b). Dopamine can entrain photoreceptor circadian oscillators and shift the circadian phase of photoreceptors that are similar but not identical to those of light itself (Cahill and Besharse 1991; Hasegawa and Cahill 1999b; Steenhard and Besharse 2000). Dopamine facilitates the transition between rod-dominate signaling pathways characteristic of scotopic conditions and cone-dominate pathways that operate under photopic conditions (Djamgoz and Wagner 1992; Krizaj 2000) and therefore, contributes to circadian rhythms of rod–cone dominance (Witkovsky et al. 1988; Wang and Mangel 1996; Manglapus et al. 1998, 1999). As a result, dopamine functions as a feedback signal from the inner retina that refines and modulates circadian control mechanisms within the photoreceptors (Ko et al. 2003). In addition, dopamine plays an important role in light adaptation of the retina that is independent from its effects on circadian oscillators (Besharse and Iuvone 1992; Cahill and Besharse 1995;Besharse et al. 2004).

As noted above, the synthesis and release of dopamine is under circadian control with more dopamine released during the day, but dopamine release is also stimulated after acute light exposure at night (Adachi et al. 1998a). Dopamine evokes a phase-dependent modulation of the CNGC affinity rhythm in chicken cone photoreceptors that is through the activation of D2 dopamine receptors (Ko et al. 2003). Exposure to dopamine or D2 agonists causes a significant decrease in the apparent affinity of CNGCs at night but has no effect on these channels during the day. It is well established that D2 receptors are pertussis toxin sensitive G protein- coupled receptors that mediate the inhibition of adenylate cyclase and cause a decrease in cAMP formation in the retina (Iuvone 1986, 1990; Stenkamp et al. 1994). However, the phase-dependent modulation of CNGCs in cone photoreceptors by dopamine does not involve pertussis toxin sensitive G proteins or cAMP signaling, as exposure to cAMP or pertussis toxin does not reverse the phase-dependent modulation of dopamine on CNGCs. This circadian modulation of cone CNGCs by dopamine is partially through the MAPK–CaMKII signaling pathway (Ko et al. 2003).

Modulation of cone cGMP-gated ion channels by somatostatin

Somatostatin (SS) is released from a class of amacrine cells that are immunoreactive for enkephalin, neurotensin, and SS, and thus, they are called ENSLI (enkephalin-, neurotensin-, and SS-like immunoreactive) amacrine cells (Morgan and Boelen 1996). There are two forms of SS: SS-14 with 14 amino acids and SS-28 with 28 amino acids, and both forms are released from ENSLI cells (Ishimoto et al. 1986; Dowton et al. 1994; Watt and Florack 1994; Yang et al. 1997). The release of SS from the ENSLI cells is under circadian control, which is high at night and low during the day in mammalian retinas (Webb et al. 1988; Peinado et al. 1990), and this rhythm is concurrent with the activities of these cells with a high sustained rate of activity in the dark and a low sustained rate of activity in the light (Morgan et al. 1994). The five SS receptors 1–5 are guanine nucleotide binding protein (G protein) coupled receptors. While all five subtypes of SS receptors are expressed in mammalian retina (Cristiani et al. 2002; Thermos 2003), the chicken retina does not express SS receptor 1 (Chen et al. 2007). Both SS-14 and SS-28 modulate cone CNGC sensitivity to cGMP that depend on circadian phase and immediate history of illumination. Both SS-14 and SS-28 decrease CNGC sensitivity to cGMP at night, which is similar to the action of dopamine via the D2 receptor and resistant to pertussis toxin. In addition, SS-28, but not SS-14, evokes a transient increase in CNGC affinity to cGMP only during the early part of the day in cone photoreceptors that have been exposed to light for 1–2 h. This transient effect by SS-28 is mediated by pertussis toxin sensitive G protein-coupled receptors and activation of phospholipase C and protein kinase C signaling cascades (Chen et al. 2007). Therefore, SS modulation of retinal cones may serve to reinforce circadian processes intrinsic to the photoreceptors, and may also contribute to more rapid adaptive responses to changes in ambient illumination.

Circadian regulation of L-type voltage-gated calcium channels

The L-type calcium channels mediate a voltage-dependent and depolarization-induced calcium influx and regulate diverse biological processes such as contraction, secretion, neurotransmission, differentiation, and gene expression in many different cell types (Abernethy and Soldatov 2002; Catterall et al. 2005). The L-type VGCCs (L-VGCCs) are composed of a pore-forming α1 subunit and auxiliary β, α2δ, and γ subunits, and they can be blocked by divalent cations (e.g. cobalt) and organic L-VGCC antagonists such as dihydropyridines, phenylalkylamines, and benzothiazepines (Catterall et al. 2005; Dolphin 2006). The α1 subunit serves as a voltage sensor to detect voltage changes across the plasma membrane, and it also controls the pore size to allow selective divalent cations to pass through. Mammalian α1 subunits are encoded by at least 10 distinct genes (Catterall et al. 2005; Dolphin 2006), and the α1C, α1D, and α1F subtypes (also known as Cav1.2, Cav1.3, and Cav1.4, respectively) are expressed in retina photoreceptors (Barnes and Kelly 2002; Morgans et al. 2005; Ko et al. 2007).

Circadian regulation of voltage-gated calcium channels in the retina

Photoreceptors are non-spiking neurons, and they release glutamate continuously in the dark as a result of depolarization-evoked activation of L-VGCCs (Barnes and Kelly 2002). Circadian regulation of L-VGCCs has been observed in gold fish retinal bipolar cells (Hull et al. 2006), chicken cone photoreceptors (Ko et al. 2007), and other non-retinal neurons (Pennartz et al. 2002). In both retinal cases, the average maximum current amplitudes of L-VGCCs are significantly larger at midnight than at midday. The activation voltages that elicit L-VGCC currents (i.e. current–voltage relationship) and the channel gating kinetics do not change throughout the day. In chicken retinas, the main factor that contributes to the circadian regulation of L-VGCC current amplitudes is the expression of functional L-VGCCα1 subunits, and both mRNA and protein expression of VGCCα1D are rhythmic (Ko et al. 2007). The Ras–MAPK–CaMKII signaling pathway serves as part of the circadian output to regulate L-VGCCs as well as CNGCs as described in the section, ‘Signaling pathways leading to the circadian regulation of cGMP-gated ion channels’, (Fig. 2). However, the varying maximum amplitudes of the L-VGCC currents are in stark contrast to the CNGC maximum currents, which remain constant throughout the day, and which instead exhibit changes in gating properties (Ko et al. 2001, 2007).

In addition to the Ras–MAPK–CaMKII pathway, the phosphatidylinositol 3 kinase (PI3K)–protein kinase B (Akt) signaling pathway also regulates the circadian functionality of L-VGCCs. The PI3K–Akt pathway regulates a vast array of cellular processes and biological functions (Shaw and Cantley 2006; Yoon et al. 2008) from post-translational modulation of proteins, protein and vesicle trafficking, cytoskeletal remodeling, to controlling cell cycles, proliferation, and survival (Blair and Marshall 1997; Lhuillier and Dryer 2002, 2003; Roth et al. 2004; Viard et al. 2004). Various ion channel activities are augmented following the activation of PI3K–Akt signaling that instigate channel protein trafficking and insertion into the plasma membrane, and these channels include kidney aquaporin 2 channels (Tajika et al. 2004), non-selective cation channels (Kanzaki et al. 1999), calcium-dependent potassium channels (Lhuillier and Dryer 2002), and L-VGCCs (Le Blanc et al. 2004). In chicken retina, the PI3K–Akt signaling pathway participates in the circadian phase-dependent modulation of L-VGCCs (Ko et al. 2009). Inhibition of PI3K–Akt in cultured photoreceptors decreases the maximum current amplitude of L-VGCCs at night but did not alter these currents during the day. Inhibitors of the PI3K–Akt pathway have no effect on the mRNA levels of L-VGCCα1D subunits, nor do they block the L-VGCCs directly in vitro. Cell surface biotinylation assays reveal that PI3K–Akt mainly affects the membrane insertion of VGCCα1D subunits (Ko et al. 2009). Activation of Akt requires a multistep process that includes phosphorylation of Thr308 in the kinase domain and Ser473 within the regulatory domain (Fayard et al. 2005). As a downstream target of PI3K, the overall activity of Akt is the result of an equilibrium between these two phosphorylation sites (Beaulieu et al. 2007). Circadian regulation of Akt activity occurs through phosphorylation of Thr308, but not on Ser473, in intact chicken retinas. The PI3K–Akt pathway, like Erk, is downstream of Ras but appears to be separate, yet, equally important in regulating L-VGCCs in retina photoreceptors (Ko et al. 2009). Hence, both Ras–PI3K–Akt and Ras–Erk signaling pathways serve as parallel output pathways to regulate the circadian rhythms of L-VGCCs (Fig. 3).

Functional significance of circadian regulation of voltage-gated calcium channels in the retina

A major functional significance of the L-VGCC rhythm is the circadian control of melatonin release. In many vertebrate species, melatonin is synthesized and secreted in the retina and is under circadian control with a higher level at night than during the day (Cahill and Besharse 1993; Bernard et al. 1997; Ivanova and Iuvone 2003b). One of the key enzymes leading to the synthesis of melatonin is AANAT, and both mRNA and protein levels of AANAT are elevated at night (for more detail on the circadian rhythm of melatonin, please see review by Iuvone et al. 2005). The dark-dependent increase in AANAT activity and melatonin synthesis requires calcium influx through L-VGCCs as illustrated when these channels are inhibited with dihydropyridines, which suppresses AANAT activity and therefore blocks the synthesis and release of melatonin (Iuvone and Besharse 1986; Cahill and Besharse 1993; Bernard et al. 1997; Ivanova and Iuvone 2003b). In avian retinas, the mechanism by which calcium influx controls melatonin synthesis and subsequent release is through cAMP levels, which peak at night (Ivanova and Iuvone 2003a). Calcium stimulates cAMP production through activation of calcium/calmodulin-dependent adenylate cyclases (Xia et al. 1993; Fukuhara et al. 2004; Iuvone et al. 2005), and L-VGCC blockers reverse this calcium-induced cAMP production (Iuvone et al. 1991, 2005). Cyclic AMP, in turn, can modulate the phosphorylation of transcription factors that augment the E-box-driven increase in AANAT mRNA (Iuvone et al. 2005). Thus, the circadian regulation of calcium influx through L-VGCCs may further contribute to the daily rhythm of AANAT and production and secretion of melatonin in the retina (Fig. 3). Hence, the L-VGCCs are not only subjected to circadian control through output pathways and regulating downstream targets, the calcium influx through L-VGCCs serves as part of the input pathways to modulate the core oscillators that further regulate rhythmic gene expression.

The photoreceptor components of electroretinograms (ERGs), the electrophysiological recordings of retinal physiology, recorded from humans as well as animals, show daily rhythms (Dearry and Barlow 1987; Hawlina et al. 1992; Lu et al. 1995; Hankins et al. 1998, 2001; Manglapus et al. 1998, 1999; McGoogan et al. 2000; Tuunainen et al. 2001; Miranda-Anaya et al. 2002; Rufiange et al. 2002; Ren and Li 2004). The ERG is one type of extracellular recording that record global electrical changes across the retina by placing recording electrodes on the surface of the eye. It is regularly used in clinical practice as well as research to examine the physiological status of the retina in response to various light stimulation (Lam 2005). As L-VGCCs are essential for neurotransmitter release in the retina, the circadian regulation of L-VGCCs in photoreceptors could contribute to the daily rhythm of the photoreceptor components of ERGs. One aspect of the role of L-VGCCs in the circadian regulation of synaptic transmission is the correlation of circadian rhythms in ribbon synapse morphology and L-VGCC currents recorded at the synaptic terminal. Ribbon synapses are specialized synaptic structures that allow for the tonic release of neurotransmitters under graded membrane potentials from retinal photoreceptors and bipolar cells, as well as hair cells in the auditory and vestibular system (Lenzi et al. 1999; Parsons and Sterling 2003) and are often located near clusters of L-VGCCs (Issa and Hudspeth 1994). In fish bipolar terminals, there is a diurnal difference in the organization of the vesicular halo around synaptic ribbons. At midnight, the vesicular halos surrounding the synaptic ribbons are more organized than during the daytime (Hull et al. 2006). Interestingly, this diurnal regulation of ribbon ultrastructure coincides with the diurnal rhythm of L-VGCCs in bipolar cells. The average peak amplitude of L-VGCCs recorded from bipolar cell terminals are significantly larger at midnight than at midday (Hull et al. 2006). Hence, the diurnal regulation of L-VGCCs in fish bipolar cells is associated with the daily changes in ribbon synapse ultrastructure (Fig. 2b).

Another physiological aspect of the L-VGCC rhythm is the circadian control of retinoschisin secretion. Retinoschisin is a 224-amino acid protein secreted mainly by retinal photoreceptors and bipolar cells and is important in the development and maintenance of retinal cytoarchitecture (Reid et al. 1999, 2003; Grayson et al. 2000; Molday et al. 2001; Reid and Farber 2005). Mutations in the retinoschisin gene (RS1) cause X-linked retinoschisis, a retinal dystrophy that features disorganization of retinal cell layers, disruption of the synaptic structures and neurotransmission between photoreceptors and bipolar cells, and progressive degeneration of rod and cone photoreceptors (Gehrig et al. 1999; Reid et al. 1999; Wang et al. 2002; Tantri et al. 2004; Zeng et al. 2004; Molday et al. 2007). In chicken retinas, mRNA and protein expression of retinoschisin are under circadian control, and inhibition of L-VGCCs with dihydropyridines dampens the circadian rhythm of retinoschisin secretion where only nighttime secretion is affected (Ko et al. 2008). Furthermore, there is a physical interaction between retinoschisin and the L-VGCCα1D subunit (Shi et al. 2009). Not only do retinoschisin and the N-terminal of the L-VGCCα1 subunit physically interact with one another, over-expression of a missense retinoschisin (RS1) mutant gene, R141G, in chicken cone photoreceptors causes a decrease in L-VGCC currents at night and dampens the channel rhythm. Therefore, there is a novel bidirectional relationship between L-VGCCs and retinoschisin: L-VGCCs regulate the circadian rhythm of retinoschisin secretion, while secreted retinoschisin feeds back to regulate L-VGCCs. Physical interactions between L-VGCCα1 subunits and retinoschisin play an important role in the membrane retention of L-VGCCα1 subunits and photoreceptor-bipolar synaptic transmission (Fig. 3; Shi et al. 2009).

Circadian regulation of L-voltage-gated calcium channels in the suprachiasmatic nucleus

As mentioned in the section, ‘The circadian oscillators in the mammalian suprachiasmatic nucleus’, the action potential firing rate of SCN neurons are under circadian control with increases in spontaneous firing during the day (Green and Gillette 1982; Shibata and Moore 1988; Welsh et al. 1995; Quintero et al. 2003; Wang and Huang 2004; Meredith et al. 2006). There are several ion channels that potentially contribute to the circadian rhythm of firing rates in SCN neurons, including the L-type calcium channels. There is a circadian regulation of intracellular calcium levels in SCN cells that results from a robust diurnal modulation of L-VGCC currents (Pennartz et al. 2002) and can be abolished with VGCC blockers (Colwell 2000). Pennartz et al. (2002) demonstrated that the current amplitude of L-VGCCs is significantly higher during the day and tightly coupled to spike generation in SCN neurons. However, the precise physiological role of this L-VGCC rhythm in SCN neuron spike generation is controversial, as others have reported that L-VGCCs may only contribute to the spike interval or the monophasic afterhyperpolarization but not spike generation (Pennartz et al. 2002; Cloues and Sather 2003; Jackson et al. 2004). Another possible role for SCN L-VGCCs is as a circadian input to synchronize the rhythmicity of the expression of clock genes such as Per2 and Bmal1, as inhibition of these channels abolishes the oscillatory patterns of Per2 and Bmal1 expression (Nahm et al. 2005). Hence, L-VGCCs could contribute to coordinating rhythmic clock gene expression through the input pathway, even though the channels themselves are regulated by the circadian clocks and serve as outputs (Ko et al. 2007). This dual role is similar to the circadian regulation of CNGCs serving in both the input and output pathways. Therefore, L-VGCCs may have a significant impact on maintaining the stability of the circadian oscillators at the cellular level, and such a model has been proposed for invertebrate circadian pacemaker cells (McMahon and Block 1987).

Circadian regulation of T-type voltage-gated calcium channels

The transient (T) type VGCCs (T-VGCC) are activated at low voltages for calcium influx into neurons, and they are responsible for the generation of normal brain rhythms as well as abnormal brain rhythms associated with numerous neurological disorders (Huguenard and Prince 1992; Tarasenko et al. 1997; Talley et al. 2000). The modulation of T-VGCCs has been implicated in sleep/wake cycles in animals. During slow wave sleep, relay neurons in the thalamus are relatively hyperpolarized in a range that activates T-VGCCs (Bal et al. 1995). Upon arousal, thalamic neurons become more depolarized because of influences from the brainstem resulting in less T-VGCC activity (Nordskog et al. 2006). There are diurnal regulations of gene expression of all three T-VGCC subtypes, Cav3.1, Cav3.2, and Cav3.3 in the mouse thalamus (Nordskog et al. 2006). While the gene expression of Cav3.1 peaks late at night corresponding to the early sleep period, Cav3.2 and Cav3.3 expression peak during the early night when mice are in their late inactive phase. Therefore, the fluctuations in T-VGCC activity are important for normal sleep patterns (Nordskog et al. 2006). In the rat SCN and cerebellum, the expression of T-VGCCs is also under circadian control (Nahm et al. 2005). In the SCN, gene expression of T-VGCCs is greatest during the transition period from day to night, which correlates to the late sleep period, while in the cerebellum, T-VGCC expression peaks in the middle of the night when these animals are most active (Nahm et al. 2005). Treatment with T-VGCC blockers shift the circadian phases of the SCN (Kim et al. 2005). Therefore, T-VGCCs contribute to the regulation of sleep–wake cycles and circadian phase-shifting.

Circadian regulation of potassium channels

Potassium channels are the most diverse ion channel class with over 100 genes linked to the pore-forming α-subunit identified to date (Kim and Hoffman 2008). They can dampen membrane excitability and set the resting membrane potential in neurons. There are four major families of K+ channels classified by their genetic homology and functional characteristics: voltage-gated; Ca2+-activated; inward rectifier; and leak K+ channels (Kim and Hoffman 2008). In photoreceptors, the dark inward current through CNGCs in the outer segment is counterbalanced by a K+ outward current in the inner segment (Molday and Kaupp 2000), which is mainly through voltage-gated K+ channels. The major subtypes of voltage-gated K+ channels present in photoreceptors are delayed-rectifier (Kv1.2, 1.3, and 2.1) and A-type transient K+ channels (Kv4.2; Pinto and Klumpp 1998). The Ca2+-activated K+ channels and outward-rectifying non-inactivating K+ channels (Kv10.2; eag2) are also found in photoreceptors (Jow and Jeng 2008; Pelucchi et al. 2008). Thus far, reports dealing with the circadian regulation of K+ channels in the retina have been confined mostly to invertebrate studies. In Aplysia retinal pacemaker neurons (not photoreceptors), there is a robust circadian rhythm of potassium currents carried by voltage-gated K+ channels (IKV), while the transient A-type and Ca2+-activated K+ currents remain constant throughout the day (Barnes and Jacklet 1997). When IKV peaks at late night (pre-dawn), the compound action potential firing frequency reaches its nadir. The circadian rhythm of IKV in turn contributes to the circadian control of the frequency of compound action potentials in pacemaker neurons. The basal retinal neurons in the eye of the mollusk Bulla gouldiana express a circadian rhythm in optic nerve impulses (Michel et al. 1993). It is the circadian regulation of IKV, but not other outward K+ channels, that drive the daily fluctuations in membrane conductance and membrane potential of these neurons (Michel et al. 1999).

In Drosophila, both Ca2+-activated (KCa) and voltage-gated K+ channels contribute to the circadian regulation of locomotor activity and sleep–wake cycles. The Slowpoke potassium channel is one type of big conductance KCa (BK) channel (Michel et al. 1999). The mRNA and protein expression of the Slowpoke binding protein show a circadian rhythm in photoreceptor cells as well as in Drosophila heads and in neurosecretory cells of the pars intercerebralis neurons (Jaramillo et al. 2004). Over-expression of Slowpoke binding protein alters the circadian-regulated locomotor activity rhythm. In addition, a point mutation in the Shaker gene, which encodes a voltage-gated K+ channel, causes shortened sleep periods and a reduced lifespan (Cirelli et al. 2005). Another voltage-gated K+ channel encoded by the Shaw gene is widely expressed in Drosophila central neurons and is known to regulate resting membrane potential (Hodge and Stanewsky 2008), and its over-expression in Drosophila clock neurons lead to arrhythmic locomotor behavior.

In the mammalian SCN, the BKs are also circadian regulated, with peak activity at night (Cloues and Sather 2003; Kuhlman and McMahon 2004; Meredith et al. 2006; Pitts et al. 2006). As the membrane potential, input conductance, and spontaneous firing frequency are rhythmic in the SCN (Schaap et al. 1999), the circadian regulation of BKs contributes to multiple circadian aspects of SCN neuronal activity, including suppressing spontaneous firing at night (Kent and Meredith 2008). Deletion of the Kcnma1 gene, which encodes the BK channel, dampens locomotor activity and physiological rhythms in mice (Kent and Meredith 2008). A fast delayed-rectifier potassium channel (FDR), encoded by the Kv3.1b and Kv3.2 genes, is also under circadian regulation in SCN neurons (Itri et al. 2005). The FDR potassium current peaks during the day that coincides with higher expression of Kv3.1b and Kv3.2 in SCN neurons at this time. Blocking FDR abolishes the daily rhythm in the firing rate of SCN neurons, and therefore, these channels are important for SCN neurons to sustain high firing frequencies through enabling rapid repolarization during the day (Itri et al. 2005). Taken together, one major function of the circadian regulation of the various K+ channels is to regulate neuron excitability, which could ultimately lead to the circadian output control of rhythmic behaviors.

Circadian regulation of Na+/K+-ATPase in the suprachiasmatic nucleus

The sodium-potassium pump (Na+/K+-ATPase) is an energy-transducing ionic pump located in the plasma membrane that transports 3 Na+ ions out of and 2 K+ ions into the cell at the expense of energy derived from ATP hydrolysis (Therien and Blostein 2000). The function of Na+/K+-ATPase is to maintain Na+ and K+ gradients across the plasma membrane, thereby contributing to the resting membrane potential in excitable cells (Therien and Blostein 2000). The Na+/K+-ATPase also plays an important role in the regulation of intracellular calcium homeostasis through an indirect interaction with the Na+-Ca2+ exchanger or inositol 1,4,5-triphosphate receptor mediated intracellular calcium stores (Tian and Xie 2008). In SCN neurons, there is a diurnal rhythm in Na+/K+-ATPase activity, which is higher during the day (Wang and Huang 2004, 2006). As the action potential firing rate is higher during the day, the concurrent higher activity of Na+/K+-ATPase is crucial in restoring the Na+ and K+ gradients and reestablishing the resting membrane potential.

Circadian regulation of a long-opening time cation channel (ILOT) in the avian pineal gland

As described in the section, ‘The circadian rhythms in the pineal gland’, the secretory cells (pinealocytes) of the pineal gland exhibit circadian rhythms in melatonin release that is high at night and inhibited by light (Deguchi 1979a,b,c; Zatz and Mullen 1988b; Zatz 1989). In mammals, the circadian rhythm of pineal physiology is directly controlled by the SCN. However, in other vertebrate species including avians, reptiles, and amphibians, pinealocytes are themselves photosensitive, and the light-sensitive circadian rhythms in melatonin release from pinealocytes persist in vitro (Robertson and Takahashi 1988a,b; Bell-Pedersen et al. 2005). Even though L-VGCCs are present in chicken pinealocytes (Henderson and Dryer 1992), inhibition of these channels only decreases evening melatonin by 40% with no apparent effect on daytime melatonin levels (Nikaido and Takahashi 1996), which is in stark contrast to the role of L-VGCCs on avian retinal melatonin as described previously (Iuvone and Besharse 1986; Cahill and Besharse 1993; Bernard et al. 1997; Ivanova and Iuvone 2003b). Interestingly, there is a non-selective cation channel unique to pinealocytes (D’Souza and Dryer 1996). The conductance of this channel is about 40 pS, and once open it remains so for a relatively long period of time (up to 20 s). Thus, this channel was aptly named ILOT (long-opening time). The ILOT channel is not voltage-, stretch-, or nucleotide-activated, and its gating properties persist in excised inside-out patches in the absence of Ca2+. The ILOT channel is permeable to calcium and active exclusively at night. ILOT activity is not suppressed by brief light pulses (D’Souza and Dryer 1996) but requires protein synthesis (D’Souza and Dryer 1997). Even though the biophysical properties of ILOT channels have been studied, unfortunately the molecular structure, amino acids, and gene sequence are still unknown. Moreover, ILOT channels are not activated by melatonin, activation of adenylate cyclase, or depleted internal calcium stores (D’Souza and Dryer 1996). One technical difficulty in investigating the molecular properties or the function of ILOT channels is that these channels are only observed in less than 1/4 of the pinealocyte population at night (D’Souza and Dryer 1996), and therefore, the ILOT channel is unlikely to be a regulatory factor in melatonin release from avian pineal glands. However, it is possible that ILOT channels could serve as a source of cation signals to synchronize and provide communication between pineal oscillators. More rigorous investigations will be required to further understand the nature and function of the ILOT channel.

Conclusion

In addition to the SCN as the master circadian oscillator in mammals, the retina and pineal gland are the two major areas that contain independent circadian oscillators especially in non-mammalian vertebrates. As ion channels are the gatekeepers of neuronal excitability, circadian regulation of ion channels governs the daily oscillations of plasma membrane excitability and action potential firing rates of SCN neurons; photosensitivity, melatonin release and retinoschisin secretion from retina photoreceptors; as well as melatonin release from pinealocytes. In invertebrates, circadian control of ion channels ultimately regulates the daily rhythms in locomotor behavior, sensitivity of olfaction, as well as learning and memory.

Thus far, how circadian oscillators regulate cellular function and physiology has been most intensively studied in non-mammalian retinal photoreceptors. Photoreceptors have endogenous circadian oscillators that can function independently of other retinal inputs (Cahill and Besharse 1993; Thomas et al. 1993; Ko et al. 2001). These circadian oscillators regulate retinomotor movement (Nagle and Burnside 1984; Pierce and Besharse 1985, 1988; Wagner et al. 1993; Burnside 2001), outer segment disc shedding (Besharse and Dunis 1983) and membrane renewal (Reme et al. 1986; Cahill and Besharse 1995), morphological changes at synaptic ribbons (Adly et al. 1999), gene expression (Korenbrot and Fernald 1989; Pierce et al. 1993; Yoshida et al. 1993; Green and Besharse 1996; Haque et al. 2002), a delayed-rectifier potassium channel (Michel et al. 1993), the affinity of CNGCs (Ko et al. 2001), the L-VGCCs (Ko et al. 2007), and the activities of MAPK and CaMKII (Ko et al. 2001) among other photoreceptor activities. The ERG is a graphical representation of electrical potential changes across the eye that is elicited by a light stimulus. The ERG has been used as an assessment of physical and clinical conditions of the retina, and hence, it is a useful technique for tracing retinal rhythmicity in vivo (Cameron et al. 2008). While L-VGCCs contribute to various components of ERGs, several retinal degenerative diseases are associated with dampened or abnormal circadian rhythms in ERGs. In the Royal College of Surgeons rat, an animal model with inherited retinal degeneration, the diurnal changes in ERG c-waves are dampened prior to the onset of retinal degeneration from postnatal days 17 to 24 (Hawlina et al. 1992; Strauss et al. 1998). Mutations in human cone–rod homeobox are associated with retinal diseases, including cone–rod dystrophy-2, retinitis pigmentosa, and Leber congenital amaurosis, which all lead to blindness (Furukawa et al. 1999; Morrow et al. 2005). In a mouse model of cone–rod homeobox mutation, the circadian rhythmicity of the ERG is abolished, and the mutant mice are not able to be entrained by light–dark cycles (Furukawa et al. 1999). Hence, circadian regulation of ion channels modulates the physiological states and function of the visual system.

Compared with other research areas in chronobiology, the circadian regulation of ion channels remains largely unexplored. For example, many parts of the molecular mechanisms linking the core oscillators (the ‘molecular clock’) to the rhythmic control of ion channels are still unknown. Disruption of components of the molecular clock causing abnormal or dampened circadian rhythmicities in animals has been demonstrated. However, the functional significance of circadian fluctuations in ion channel activities that ultimately lead to the daily rhythmicities in neuronal activities of controlling locomotor activity, synaptic plasticity, learning and memory, and even sleep–wake cycles, has yet to be explored. In addition, the participation of ion channels in circadian entrainment is not clear. Addressing the questions above, as well as identification and characterization of other ion channels that are potentially under circadian control, will be important for future directions of research, as ion channels have been utilized as therapeutic targets for various diseases. Understanding the circadian regulation of ion channels will ultimately benefit the future development of therapeutic strategies in the treatment of sleep disorders, cardiovascular diseases, and other illness linked to circadian misalignment (Scheer et al. 2009).

Abbreviations used

AANAT

arylalkylamine N-acetyltransferase

Akt

protein kinase B

BK

big conductance KCa

BMAL

brain and muscle, ARNT-like

CaMKII

calcium–calmodulin kinase II

CLOCK

circadian locomotor output cycles kaput

CNGC

cGMP-gated cation channel

CRY

cryptochrome

ENSLI cells

enkephalin-, neurotensin-, and somatostatin-like immunoreactive cells

ERG

electroretinogram

FDR

fast delayed-rectifier

ILOT

long-opening time cation channel

L-VGCC

L-type VGCC

MAPK

mitogen-activated protein kinase

PER

period

PI3K

phosphatidylinositol 3 kinase

REV-ERBα

reverse orientation c-erbA-1 gene alpha; an orphan nuclear receptor

SCN

suprachiasmatic nucleus

SS

somatostatin

T-VGCC

transient (T)-type VGCC

VGCC

voltage-gated calcium channels

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