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

Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) play a central role in regulating intracellular calcium signals in response to a variety of internal/external cues. Dysregulation of IP3R signaling is the underlying cause for numerous pathological conditions. It is well established that the activities of IP3Rs 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 sub-types, remains largely unexplored. In this report, we investigate the effects of more chronic stimulation and tonic activity of PKA on the expression of IP3R sub-types. We demonstrate that the expression of IP3R1 is augmented upon prolonged activation of PKA or upon ectopic over-expression of CREB without altering IP3R2 and IP3R3 abundance. Conversely, inhibition of PKA or blocking CREB diminished IP3R1 expression. We also demonstrate that agonist-induced Ca2+-release mediated by IP3R1 is significantly attenuated upon blocking CREB. Moreover, CREB by regulating the expression of KRAS-induced actin-interacting protein (KRAP) ensures proper localization and licensing of IP3R1. Overall, we report a crucial role for CREB in governing both the expression and proper localization of IP3R1.