A Specific Role For The Rev-Erb Alpha-Controlled L-Type Voltage-Gated Calcium Channel Ca(V)1.2 In Resetting The Circadian Clock In The Late Night

Within the suprachiasmatic nucleus (SCN) of the hypothalamus, circadian timekeeping and resetting have been shown to be largely dependent on both membrane depolarization and intracellular second-messenger signaling. In both of these processes, voltage-gated calcium channels (VGCCs) mediate voltage-dependent calcium influx, which propagates neural impulses by stimulating vesicle fusion and instigates intracellular pathways resulting in clock gene expression. Through the cumulative actions of these processes, the phase of the internal clock is modified to match the light cycle of the external environment. To parse out the distinct roles of the L-type VGCCs, we analyzed mice deficient in Ca(v)1.2 (Cacna1c) in brain tissue. We found that mice deficient in the Ca(v)1.2 channel exhibited a significant reduction in their ability to phase-advance circadian behavior when subjected to a light pulse in the late night. Furthermore, the study revealed that the expression of Ca(v)1.2 mRNA was rhythmic (peaking during the late night) and was regulated by the circadian clock component REV-ERB alpha. Finally, the induction of clock genes in both the early and late subjective night was affected by the loss of Ca(v)1.2, with reductions in Per2 and Per1 in the early and late night, respectively. In sum, these results reveal a role of the L-type VGCC Ca(v)1.2 in mediating both clock gene expression and phase advances in response to a light pulse in the late night.