A light-induced small G-protein gem limits the circadian clock phase-shift magnitude by inhibiting voltage-dependent calcium channels

Masahiro Matsuo; Kazuyuki Seo; Akiyuki Taruno; Yasutaka Mizoro; Yoshiaki Yamaguchi; Masao Doi; Rhyuta Nakao; Hiroshi Kori; Takaya Abe; Harunori Ohmori; Keiko Tominaga; Hitoshi Okamura

doi:10.1016/j.celrep.2022.110844

A light-induced small G-protein gem limits the circadian clock phase-shift magnitude by inhibiting voltage-dependent calcium channels

Cell Rep. 2022 May 24;39(8):110844. doi: 10.1016/j.celrep.2022.110844.

Authors

Affiliations

¹ Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan; Department of Psychiatry, Shiga University of Medical Sciences, Otsu City, Shiga, Japan.
² Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
³ Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan; Department of Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁴ Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan.
⁵ Department of Complexity Science and Engineering, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
⁶ Department of Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.
⁷ Department of Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁸ Department of Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
⁹ Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan; Department of Neuroscience, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: okamura.hitoshi.4u@kyoto-u.ac.jp.

PMID: 35613591
DOI: 10.1016/j.celrep.2022.110844

Abstract

Calcium signaling is pivotal to the circadian clockwork in the suprachiasmatic nucleus (SCN), particularly in rhythm entrainment to environmental light-dark cycles. Here, we show that a small G-protein Gem, an endogenous inhibitor of high-voltage-activated voltage-dependent calcium channels (VDCCs), is rapidly induced by light in SCN neurons via the calcium (Ca²⁺)-mediated CREB/CRE transcriptional pathway. Gem attenuates light-induced calcium signaling through its interaction with VDCCs. The phase-shift magnitude of locomotor activity rhythms by light, at night, increases in Gem-deficient (Gem^-/-) mice. Similarly, in SCN slices from Gem^-/- mice, depolarizing stimuli induce larger phase shifts of clock gene transcription rhythms that are normalized by the application of an L-type VDCC blocker, nifedipine. Voltage-clamp recordings from SCN neurons reveal that Ca²⁺ currents through L-type channels increase in Gem^-/- mice. Our findings suggest that transcriptionally activated Gem feeds back to suppress excessive light-evoked L-type VDCC activation, adjusting the light-induced phase-shift magnitude to an appropriate level in mammals.

Keywords: CP: Neuroscience; Gem; RGK; circadian clock; light-induced; phase-shift; small G-protein; suprachiasmatic nucleus; voltage-dependent calcium channels.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium Channels, L-Type / metabolism
Circadian Clocks*
Circadian Rhythm / physiology
Mice
Mice, Inbred C57BL
Monomeric GTP-Binding Proteins* / metabolism
Suprachiasmatic Nucleus / metabolism

Substances

Calcium Channels, L-Type
Monomeric GTP-Binding Proteins