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 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 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 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 (IP3R1) is augmented upon prolonged activation of PKA or upon ectopic overexpression of cyclic AMP-response element-binding protein (CREB) without altering IP3R2 and IP3R3 abundance. By contrast, 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 of CREB. Moreover, CREB - by regulating the expression of KRAS-induced actin-interacting protein (KRAP) - ensures correct localization and licensing of IP3R1. Overall, we report a crucial role for CREB in governing both the expression and correct localization of IP3R1. This article has an associated First Person interview with the first author of the paper.

Modulation of cytosolic calcium signaling by protein kinase A-mediated phosphorylation of inositol 1, 4, 5-trisphosphate receptors

Calcium release via intracellular Ca2+ release channels is a central event underpinning the generation of numerous, often divergent physiological processes. In electrically non-excitable cells, this Ca2+ release is brought about primarily through activation of inositol 1,4,5-trisphosphate receptors and typically takes the form of calcium oscillations. It is widely believed that information is carried in the temporal and spatial characteristics of these signals. Furthermore, stimulation of individual cells with different agonists can generate Ca2+ oscillations with dramatically different spatial and temporal characteristics. Thus, mechanisms must exist for the acute regulation of Ca2+ release such that agonist-specific Ca2+ signals can be generated. One such mechanism by which Ca2+ signals can be modulated is through simultaneous activation of multiple second messenger pathways. For example, activation of both the InsP3 and cAMP pathways leads to the modulation of Ca2+ release through protein kinase A mediated phosphoregulation of the InsP3R. Indeed, each InsP3R subtype is a potential substrate for PKA, although the functional consequences of this phosphorylation are not clear. This review will focus on recent advances in our understanding of phosphoregulation of InsP3R, as well as the functional consequences of this modulation in terms of eliciting specific cellular events.