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IRBIT expands signaling repertoire: Regulation of the Ca2+‐activated Cl− channel Bestrophin 2 by synergy between Ca2+ and cAMP at membrane contact sites

The scaffolding protein IRBIT (Inositol 1,4,5‐Trisphosphate (IP3) Receptor Released with IP3) regulates the surface expression and activates several transporters, including NBCe1‐B, NHE3, CFTR, and SLC26A6, to coordinate secretory cells fluid and HCO3− secretion. IRBIT also mediates the synergy between cAMP and Ca2+ signaling. One mechanism involves PKAmediated phosphorylation of the IP3Rs that dissociate IRBIT from the IP3Rs and makes it available to activate the transporters. However, whether IRBIT affect Ca2+ and cAMP activation of the transporters and the molecular mechanism of such a regulation is not known. Here, we discovered that IRBIT is a potent activator of the Ca2+‐activated Cl− channel Bestrophin 2 (Best2), but not of Best1. IRBIT achieves this by two mechanisms. IRBIT recruits Best2 to the ER/PM junctions to increase surface expression of Best2 and increase the Ca2+‐activated Clcurrent density. At the ER/PM junctions IRBIT assembles a complex of Best2‐Adenylys cyclase 8‐PKA to confer Best2 regulation by the cAMP/PKA pathway. PKA‐mediated phosphorylation prominently increases Best2 apparent affinity for Ca2+. Best2 regulation by PKA requires intact ER/PM junctions with dissociation of the junction by knockdown of ER/PM junctions tether proteins eliminates activation of Best2 by IRBIT and regulation by PKA. Notably, activation of Best2 by Ca2+‐mobilizing receptors is markedly reduced in the salivary gland ducts of IRBIT−/− mice. These findings show the importance of localization in the ER/PM junctions for synergy in signaling and how IRBIT expands signaling repertoire by converting purely Ca2+‐activated protein to a Ca2+‐activated and cAMP/PKA regulated protein.