CREB regulates the expression of Type 1 Inositol 1,4,5-trisphosphate receptors

ABSTRACT Inositol 1,4,5-trisphosphate (IP 3 ) receptors (IP 3 Rs) play a central role in regulating intracellular calcium signals in response to a variety of internal/external cues. Dysregulation of IP 3 R signaling is the underlying cause for numerous pathological conditions. It is also well established that the activity of IP 3 Rs is governed by several post-translational modifications including phosphorylation by protein kinase A (PKA). However, the long-term effects of PKA activation on expression of IP 3 R sub-types, remains largely unexplored. In this report, we investigate the effect of chronic activation of PKA on expression of IP 3 R sub-types. We demonstrate that expression of IP 3 R1 is augmented upon prolonged activation of PKA or upon ectopic over-expression of CREB but does not alter IP 3 R2 and IP 3 R3 sub-type abundance. Conversely, inhibition of PKA or blocking endogenous CREB diminished IP 3 R1 expression. We also demonstrate that agonist-induced Ca 2+ -release mediated by IP 3 R1 is significantly attenuated upon blocking endogenous CREB. Moreover, CREB by regulating the expression of KRAS-induced actin-interacting protein (KRAP) ensures proper localization and licensing of IP 3 R1. Overall, we report a crucial role for CREB in governing both the expression and proper localization of IP 3 R1. Summary statement We report a critical role of CREB in regulating the expression and proper localization of IP 3 R1. Agonist-induced Ca 2+ release and Ca 2+ puffs generated by IP 3 R1 are diminished upon blocking the function of endogenous CREB.