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bioRxiv · 10.1101/2021.05.05.442804

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

Arige, V.·Terry, L. E.·Knebel, T. R.·Wagner, L. E.·Yule, D. I.
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Abstract

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 also well established that the activity of IP3Rs 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 IP3R sub-types, remains largely unexplored. In this report, we investigate the effect of chronic activation of PKA on expression of IP3R sub-types. We demonstrate that expression of IP3R1 is augmented upon prolonged activation of PKA or upon ectopic over-expression of CREB but does not alter IP3R2 and IP3R3 sub-type abundance. Conversely, inhibition of PKA or blocking endogenous CREB diminished IP3R1 expression. We also demonstrate that agonist-induced Ca2+-release mediated by IP3R1 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 IP3R1. Overall, we report a crucial role for CREB in governing both the expression and proper localization of IP3R1. Summary statementWe report a critical role of CREB in regulating the expression and proper localization of IP3R1. Agonist-induced Ca2+ release and Ca2+ puffs generated by IP3R1 are diminished upon blocking the function of endogenous CREB.

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Arige, V., Terry, L. E., Knebel, T. R., Wagner, L. E., Yule, D. I.. 2021-05-05. CREB regulates the expression of Type 1 Inositol 1,4,5-trisphosphate receptors. https://doi.org/10.1101/2021.05.05.442804

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