Circadian Regulation of cGMP-Gated Channels of Vertebrate Cone Photoreceptors: Role of cAMP and Ras

Feb 13, 2004The Journal of neuroscience : the official journal of the Society for Neuroscience

Daily rhythm controls light-sensitive channels in vertebrate color-detecting eye cells: role of cAMP and Ras signals

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Abstract

Circadian oscillators in chicken cone photoreceptors regulate cGMP-gated cationic channels (CNGCs) to have a higher affinity for cGMP during the subjective night.

cAMP is involved in the circadian control pathway for CNGCs, impacting their gating properties.
Activation of Erk and Ras by cAMP occurs more frequently at night in cone photoreceptors.
Inhibitors of Ras and MEK block the circadian rhythms in CNGC gating and the effects of cAMP.
cAMP influences Ras and Erk activation within minutes, but changes in CNGC modulation take over an hour.
The effects of cAMP on CNGCs do not change rhythmic patterns of cPer2 mRNA.

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Circadian oscillators in chicken cone photoreceptors regulate the gating properties of cGMP-gated cationic channels (CNGCs) such that they have a higher apparent affinity for cGMP during the subjective night. Here we show that cAMP, acting through protein kinase A (PKA), Ras, and Erk, is part of the circadian output pathway controlling CNGCs. Endogenous and exogenous cAMP cause activation of Erk and Ras, which are more active at night in cones, and increase the apparent affinity of CNGCs for cGMP. The Ras farnesyl transferase inhibitor manumycin-A, and a dominant-negative form of Ras (RasN17) block the circadian rhythms in CNGC gating, as well as the effects of cAMP. A dominant-negative form of the MEK kinase B-Raf also blocks circadian and cAMP modulation of CNGCs. The circadian output pathway modulating CNGC channels is comprised in part of cAMP --> PKA --> Ras --> B-Raf --> MEK --> Erk --> --> CNGCs. cAMP activation of Ras and Erk occur within minutes, whereas modulation of CNGCs requires >1 hr. However, cAMP protagonists do not alter rhythms in cPer2 mRNA, and their effects on CNGCs cannot be attributed to clock phase-shifting.

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Circadian Regulation of cGMP-Gated Channels of Vertebrate Cone Photoreceptors: Role of cAMP and Ras

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