Reciprocal Relationship Between Calcium Signaling and Circadian Clocks: Implications for Calcium Homeostasis, Clock Function, and Therapeutics

Abstract

In animals, circadian clocks impose a daily rhythmicity to many behaviors and physiological processes. At the molecular level, circadian rhythms are driven by intracellular transcriptional/translational feedback loops (TTFL). Interestingly, emerging evidence indicates that they can also be modulated by multiple signaling pathways. Among these, Ca²⁺ signaling plays a key role in regulating the molecular rhythms of clock genes and of the resulting circadian behavior. In addition, the application of in vivo imaging approaches has revealed that Ca²⁺ is fundamental to the synchronization of the neuronal networks that make up circadian pacemakers. Conversely, the activity of circadian clocks may influence Ca²⁺ signaling. For instance, several genes that encode Ca²⁺ channels and Ca²⁺-binding proteins display a rhythmic expression, and a disruption of this cycling affects circadian function, underscoring their reciprocal relationship. Here, we review recent advances in our understanding of how Ca²⁺ signaling both modulates and is modulated by circadian clocks, focusing on the regulatory mechanisms described in Drosophila and mice. In particular, we examine findings related to the oscillations in intracellular Ca²⁺ levels in circadian pacemakers and how they are regulated by canonical clock genes, neuropeptides, and light stimuli. In addition, we discuss how Ca²⁺ rhythms and their associated signaling pathways modulate clock gene expression at the transcriptional and post-translational levels. We also review evidence based on transcriptomic analyzes that suggests that mammalian Ca²⁺ channels and transporters (e.g., ryanodine receptor, ip3r, serca, L- and T-type Ca²⁺ channels) as well as Ca²⁺-binding proteins (e.g., camk, cask, and calcineurin) show rhythmic expression in the central brain clock and in peripheral tissues such as the heart and skeletal muscles. Finally, we discuss how the discovery that Ca²⁺ signaling is regulated by the circadian clock could influence the efficacy of pharmacotherapy and the outcomes of clinical interventions.

Keywords: Drosophila; E-box; biological clocks; chronomedicine; circadian rhythms; daily rhythms.

FIGURE 1

Ca²⁺ signaling modulates the core components of the circadian clock. (A) In Drosophila and mammals, intracellular cytosolic Ca²⁺ rhythms are regulated by external signals such as light stimuli and neuropeptides. (B) In the SCN, external signals may affect the TTFL via the G_q-Ca²⁺ pathway. In turn, Ca²⁺ signaling via CREB and the regulation of the phosphorylation state (C) and proteasomal degradation (D) of clock proteins, orchestrate the effect of Ca²⁺ on the circadian clock in Drosophila and mammals. BMAL1, Brain and Muscle ARNT-Like 1, ortholog of Drosophila Cycle gene; CaMK, Ca²⁺/calmodulin-dependent protein kinase. CLOCK, Circadian Locomotor Output Cycles Kaput; CREB, cAMP response element-binding protein; CRE elements, cAMP response elements; CRY, cryptochrome; E-box, circadian enhancer box; ER, endoplasmic reticulum; PER, PERIOD protein; PKC, protein kinase C; ROR-α, retinoid-related orphan receptor alpha; TIM, TIMELESS protein.

FIGURE 2

Circadian clocks impose a daily rhythm on intracellular Ca²⁺ signaling. (A) Photic inputs via CRY or other signaling molecules such as PLC cause a phase-shift in the expression of molecular clock components in the mammalian and Drosophila central clocks. In turn, TTFL regulate cytosolic Ca²⁺ rhythms. In SCN neurons, circadian oscillations of Ca²⁺ levels are also dependent on the mobilization of Ca²⁺ from the endoplasmic reticulum. (B) Circadian clocks impose a daily rhythm of expression to a large number of components of the Ca²⁺ signaling pathway by acting at transcriptional or post-transcriptional levels (including by regulating alternative splicing in Drosophila and microRNA in mice). In addition, in mice, the Ca²⁺/calcineurin/NFAT pathway exhibits a rhythmic activity in peripheral clocks, such as the one present in skeletal muscle or heart, which is probably mediated by inputs from the central clock. IP₃R, inositol 1,4,5-triphosphate Receptor; NFAT, nuclear factor of activated T-cells; RORE, ROR response elements. RCAN1, regulator of calcineurin 1. RyR, ryanodine receptor. SERCA, sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase. See Figure 1 for other abbreviations.

FIGURE 3

Rhythmic expression of components of the Ca²⁺ signaling pathway in human tissues. Schematic showing tissue-specific circadian expression of Ca²⁺-associated proteins and of Ca²⁺ channels and transporters in peripheral human tissues. Based on data from Ruben et al. (2018) (http://circadb.hogeneschlab.org/human).