A Specific Role for the REV-ERBα–Controlled L-Type Voltage-Gated Calcium Channel Ca_V1.2 in Resetting the Circadian Clock in the Late Night

Abstract

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 VGCC, 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 phaseadvance 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-ERBα. Finally, induction of clock genes in the early and late subjective night were each 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.

Entrainment of Circadian Rhythms to Temperature Reveals Amplitude Deficits in Fibroblasts from Patients with Bipolar Disorder and Possible Links to Calcium Channels

“…We reported previously that the BD-associated differences in amplitude under lithium-treated conditions involved calcium [13] and ERK signaling [12], pathways involved in photic entrainment in the SCN [14, 15, 18, 19]. The relative decrease in amplitude in the BD samples under both lithium treatment and entrained conditions may imply a loss of function in one or more of these pathways in BD.…”

“…Phase advances occur through glutamate signals to the master clock in the suprachiasmatic nucleus (SCN) that activate voltage-dependent LTCC, and subsequent stimulation of protein kinase G [14]. Mutant mice with forebrain selective knockout of Cacna1c expression show normal circadian rhythms under constant dark conditions, but they show a reduced ability to phase advance after a light pulse in the late night [18]. Both phase delay and phase advance pathways converge on the ERK to induce PER1/2 expression [19].…”

Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder

“…Its loss affects the ability to phase advance wheel running behavior in mouse after a light pulse and impairs the induction of Per2 and Per1 expression (26). In multiple GWASs (genome-wide association studies), CACNA1C has shown genome-wide significant associations to BP (27)(28)(29) as well as to other psychiatric disorders (27).…”

Lithium effects on circadian rhythms in fibroblasts and suprachiasmatic nucleus slices from Cry knockout mice

“…Also, lithium may affect circadian rhythms through signaling pathways other than GSK-3β. For example, chronic treatment of astrocytes with lithium causes a pronounced inhibition of K + -mediated increase in intracellular Ca 2+ , which is known to affect circadian period and other rhythm properties [17, 21, 25]. Further investigations are necessary to fully understand the signaling pathways through which lithium affects circadian rhythms.…”