KRAP tethers IP3 receptors to actin and licenses them to evoke cytosolic Ca2+ signals

Regulation of IP3 receptors (IP(3)Rs) by IP3 and Ca2+ allows regenerative Ca2+ signals, the smallest being Ca2+ puffs, which arise from coordinated openings of a few clustered IP(3)Rs. Cells express thousands of mostly mobile IP(3)Rs, yet Ca2+ puffs occur at a few immobile IP3R clusters. By imaging cells with endogenous IP(3)Rs tagged with EGFP, we show that KRas-induced actin-interacting protein (KRAP) tethers IP(3)Rs to actin beneath the plasma membrane. Loss of KRAP abolishes Ca2+ puffs and the global increases in cytosolic Ca2+ concentration evoked by more intense stimulation. Over-expressing KRAP immobilizes additional IP3R clusters and results in more Ca2+ puffs and larger global Ca2+ signals. Endogenous KRAP determines which IP(3)Rs will respond: it tethers IP3R clusters to actin alongside sites where store-operated Ca2+ entry occurs, licenses IP(3)Rs to evoke Ca2+ puffs and global cytosolic Ca2+ signals, implicates the actin cytoskeleton in IP3R regulation and may allow local activation of Ca2+ entry. Calcium signals initiated by IP3 receptors in ER membranes regulate most cellular activities. Here, the authors show that KRas-induced actininteracting protein (KRAP) tethers a small subset of IP3 receptors to actin and licenses them to evoke cytosolic calcium signals.