IP3 Receptor-Dependent Cytoplasmic Ca2+ Signals Are Tightly Controlled by Cavβ3

Abstract

Voltage-gated calcium channels (Cavs) are major Ca2+ entry pathways in excitable cells. Their b subunits facilitate membrane trafficking of the channel’s ion-conducting a1 pore and modulate its gating properties. We report that one b subunit, b3, reduces Ca2+ release following stimulation of phospholipase C-coupled receptors and inositol 1,4,5-trisphosphate (IP3) formation. This effect requires the SH3-HOOK domain of Cavb3, includes physical b3/IP3 receptor interaction, and prevails when agonist-induced IP3 formation is bypassed by photolysis of caged IP3. In agreement with b3 acting as a brake on Ca2+ release, fibroblast migration is enhanced in vitro, and in vivo, closure of skin wounds is accelerated in the absence of b3. To mediate specific physiological responses and to prevent Ca2+ toxicity, cytoplasmic Ca2+ signals must be tightly controlled. The described function of b3, unrelated to its function as a Cav subunit, adds to this tight control.