Abstract
The ubiquitous Ca2+ sensor calmodulin (CaM) binds and regulates many proteins, including ion channels, CaM kinases, and calcineurin, according to Ca2+-CaM levels. What regulates neuronal CaM levels, is, however, unclear. CaM-binding transcription activators (CAMTAs) are ancient proteins expressed broadly in nervous systems and whose loss confers pleiotropic behavioral defects in flies, mice, and humans. Using Caenorhabditis elegans and Drosophila, we show that CAMTAs control neuronal CaM levels. The behavioral and neuronal Ca2+ signaling defects in mutants lacking camt-1, the sole C. elegans CAMTA, can be rescued by supplementing neuronal CaM. CAMT-1 binds multiple sites in the CaM promoter and deleting these sites phenocopies camt-1. Our data suggest CAMTAs mediate a conserved and general mechanism that controls neuronal CaM levels, thereby regulating Ca2+ signaling, physiology, and behavior.
Highlights
Calmodulin-binding transcription activators (CAMTAs) are a highly conserved family of Ca2+-regulated transcription factors[1]
By combining cell-type specific transcriptional profiling of these neurons with chromatin immunoprecipitation (ChIP) analysis of CAMT-1’s DNA-binding sites, we find that CAMT-1 upregulates the expression of CaM to control neural activity and behaviours
CAMT-1 has the characteristic domain architecture of CAMTAs1: a DNA binding domain (CG-1), an immunoglobulin-like fold (IPT/TIG) similar to those found in non-specific DNA-binding/dimerization domains of other transcription factors, ankyrin repeats (ANKs), a putative Ca2+-dependent CaM binding domain (CaMBD) and multiple IQ motifs that are thought to bind CaM in a Ca2+independent manner (Fig. 1a, Extended Data Fig. 1b-c,23,24)
Summary
Calmodulin-binding transcription activators (CAMTAs) are a highly conserved family of Ca2+-regulated transcription factors[1]. We show here that the C. elegans ortholog of CAMTA, CAMT-1, regulates neuronal Ca2+ signaling by controlling CaM expression. A variety of behaviours are dependent on CAMT-1, and Ca2+ imaging in multiple neurons reveals that neural activity is abnormal in camt-1 mutants. By combining cell-type specific transcriptional profiling of these neurons with chromatin immunoprecipitation (ChIP) analysis of CAMT-1’s DNA-binding sites, we find that CAMT-1 upregulates the expression of CaM to control neural activity and behaviours. It is pivotal to diverse processes, including metabolic homeostasis, protein folding, apoptosis, vesicular fusion, and control of neuronal excitability[15,16], for example through regulation of CaM kinase II activity. Cellular levels of CaM are limiting, compared to the concentration of CaM binding proteins[17], and changes in CaM levels are likely to impact Ca2+/CaM regulation of downstream targets[18]. Our results identify CAMTA as a CaM regulator in neurons, and suggest CAMT-1 can both promote CaM expression and repress it, in a feedback loop by which CaM can negatively control its own expression by binding CAMT-1
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