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Fig. 2

Fig. 2. From: Circadian regulation of ion channels and their functions.

(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.

Gladys Y.-P. Ko, et al. J Neurochem. ;110(4):1150.
Fig. 1

Fig. 1. From: Circadian regulation of ion channels and their functions.

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).

Gladys Y.-P. Ko, et al. J Neurochem. ;110(4):1150.
Fig. 3

Fig. 3. From: Circadian regulation of ion channels and their functions.

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.

Gladys Y.-P. Ko, et al. J Neurochem. ;110(4):1150.

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