CREB regulates the expression of type 1 inositol 1,4,5-trisphosphate receptors

Inositol 1,4,5-trisphosphate (IP3) receptors (IP(3)Rs) play a central role in regulating intracellular Ca2+ signals in response to a variety of internal and external cues. Dysregulation of IP3R signaling is the underlying cause for numerous pathological conditions. It is well established that the activities of IP(3)Rs are governed by several post-translational modifications, including phosphorylation by protein kinase A (PKA). However, the long-term effects of PKA activation on expression of IP3R subtypes remains largely unexplored. In this report, we investigate the effects of chronic stimulation and tonic activity of PKA on the expression of IP3R subtypes. We demonstrate that expression of the type 1 IP3R (IP(3)R1) is augmented upon prolonged activation of PKA or upon ectopic overexpression of cyclic AMP-response element-binding protein (CREB) without altering IP(3)R2 and IP(3)R3 abundance. By contrast, inhibition of PKA or blocking CREB diminished IP(3)R1 expression. We also demonstrate that agonist-induced Ca2+-release mediated by IP(3)R1 is significantly attenuated upon blocking of CREB. Moreover, CREB by regulating the expression of KRAS-induced actin-interacting protein (KRAP) - ensures correct localization and licensing of IP(3)R1. Overall, we report a crucial role for CREB in governing both the expression and correct localization of IP(3)R1.