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 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 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 Cavβ3, includes physical β3/IP₃ receptor interaction, and prevails when agonist-induced IP₃ formation is bypassed by photolysis of caged IP₃. In agreement with β3 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 β3. To mediate specific physiological responses and to prevent Ca²⁺ toxicity, cytoplasmic Ca²⁺ signals must be tightly controlled. The described function of β3, unrelated to its function as a Cav subunit, adds to this tight control.

Keywords: Ca(2+) release; Ca(2+) signaling; Cavβ2; Cavβ3; Cavβ3 KO; IP(3) binding; IP(3) receptor; cell migration; voltage-gated Ca(2+) channel; wound healing.