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

Summary Voltage-gated calcium channels (Cavs) are major Ca 2+ entry pathways in excitable cells. Their β subunits facilitate membrane trafficking of the channel's ion-conducting α1 pore and modulate its gating properties. We report that one β subunit, β3, reduces Ca 2+ release following stimulation of phospholipase C-coupled receptors and inositol 1,4,5-trisphosphate (IP 3 ) formation. This effect requires the SH3-HOOK domain of Cavβ3, includes physical β3/IP 3 receptor interaction, and prevails when agonist-induced IP 3 formation is bypassed by photolysis of caged IP 3 . In agreement with β3 acting as a brake on Ca 2+ release, fibroblast migration is enhanced in vitro , and in vivo , closure of skin wounds is accelerated in the absence of β3. To mediate specific physiological responses and to prevent Ca 2+ toxicity, cytoplasmic Ca 2+ signals must be tightly controlled. The described function of β3, unrelated to its function as a Cav subunit, adds to this tight control.