Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development

Abstract

The identification of a gain-of-function mutation in CACNA1C as the cause of Timothy Syndrome (TS), a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted unexpected roles for the L-type voltage-gated Ca 2+ The broad array of abnormalities within nonexcitable tissues in Timothy Syndrome (TS) patients (1), however, revealed that Ca V 1.2 controls critical, yet previously unknown, roles in multiple nonexcitable tissues. Identified as a novel cardiac arrhythmia syndrome associated with syndactyly and dysmorphic facial features (2), the TS defect was discovered to be a specific gain-of-function mutation (G406R) in CACNA1C, the gene encoding Ca V 1.2. The mutation greatly slows channel inactivation, and thereby prolongs cellular repolarization in cardiac myocytes, which provided a clear rationale for the cardiac arrhythmias. Yet how Ca V 1.2 affects nonexcitable cells, as indicated by additional phenotypes documented in TS, such as small teeth, baldness at birth, and dysmorphic facial features, is unclear. These phenotypes were not consistent with previously understood roles for Ca V 1.2. Here, we

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…For example, Ca V 1.2 is expressed in pharyngeal arches within the subset of cells that give rise to jaw primordia. Ca 2+ influx through Ca V 1.2 regulates jaw development and affects cellular hypertrophy and hyperplasia in the mandible (Ramachandran et al, 2013).…”

Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency–induced bone loss

“…In a previous study, increased Ca 2+ influx through the TS-mutant Ca V 1.2 (Ca V 1.2 TS ) channel in mandibular chondrocytes was shown in zebrafish and mouse models to recapitulate the macrognathia observed in TS patients (4). As the mandible is unique among skeletal elements in the skull to derive from endochondral ossification, we hypothesized that Ca V 1.2 may influence bone development more broadly.…”

“…We characterized the expression profile of Ca V +/-mice are viable and fertile without obvious differences in any aspect of development (13) and only minor differences in morphology (4). The lacZ expression in Ca V 1.2 +/lacZ mice thereby provides an accurate picture of the temporospatial Ca V 1.2 expression pattern during development and definitive identification of Ca V 1.2-expressing cells.…”

Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome

“…Differences in the alpha or the beta subunit clones, the amount of co-expressed beta subunits or the different expression systems used in the two studies might explain these variances in the electrophysiological phenotype.Several studies point towards a role of CACNA1C expression and the mediated Ca 2+ flux in the embryonic and neuronal development[35]. A recent study suggests that jaw development might also be influenced by altered Cav1.2 currents[36]. Here, currents mediated by Cav1.2 regulate jaw development and gain-or loss-of-function in the calcium channels led to misdeveloped jaws.…”