IP3-dependent Ca2+ signals are tightly controlled by Cavβ3, but not by Cavβ1, 2 and 4

Independent of its function as a subunit of voltage-gated Ca2+ channels, the Cav beta 3 subunit desensitizes fibro-blasts and pancreatic beta-cells to low concentrations of inositol-1,4,5-trisphosphate (IP3). This alters agonist-induced Ca2+ signaling and cellular functions, for example, insulin secretion and wound healing. A total of four Cav beta subunits exist, Cav beta 1, Cav beta 2, Cav beta 3, and Cav beta 4. To investigate whether the other Cav beta subunits, like Cav beta 3, can desensitize cells to IP3 and thereby modulate Ca2+ signaling, we expressed the cDNAs of Cav beta 1, Cav beta 2, Cav beta 3, and Cav beta 4 in COS-7 cells lacking endogenous Cav beta proteins. ATP stimulation of these cells results in the release of Ca2+ from intracellular stores. This receptor-mediated Ca2+ release is significantly decreased by Cav beta 3 but not by Cav beta 1, Cav beta 2, and Cav beta 4. Electrophysiological recordings of voltage-dependent Ca2+ currents from fibroblasts show a small Ca2+ current, the amplitude of which is slightly but not significantly smaller in fibroblasts from Cav beta 2 gene-deficient animals than in fibroblasts from wild-type animals. Compared with fibroblasts from wild-type animals, Ca2+ release is not significantly increased in Cav beta 2-deficient fibroblasts, in contrast to Ca2+ release in Cav beta 3-deficient fibroblasts. In summary, our results show that desensitization of cells to low concentrations of IP3 is a specific property of Cav beta 3 that is not shared by other Cav beta subunits.