IRBIT regulates the WNK/SPAK pathway

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IRBIT (inositol‐1,4,5‐trisphosphate [IP3] receptors binding protein released with IP3) was discovered as an inhibitor of IP3 receptors and was later shown to activate the Na+‐HCO3− co‐transporter NBCe1B (also known as pNBC1). More recently, we showed that IRBIT plays a major role in epithelia to stimulate epithelial fluid and HCO3− secretion. IRBIT functions to coordinates epithelial fluid and electrolyte transport by stimulating the transporters NBCe1B and CFTR in the pancreatic duct. Another major regulatory pathway in epithelia is the WNK/SPAK kinases pathway that functions to inhibit epithelial fluid and electrolyte transport. This pathway plays a critical role in the control of systemic electrolyte metabolism and blood pressure. In many cases the WNKs phosphorylate SPAK, which, in turn, acts to phosphorylate several transporters and inhibit their activity primarily by increasing their endocytosis and reducing their surface expression. A central question is the interplay between the relative roles of the stimulatory IRBIT and inhibitory WNK/SPAK pathways in epithelial function. To address this question, we examined the effect of WNKs, SPAK and IRBIT in regulating the activity of NBCe1B and CFTR in model systems and secretory ducts. We found that WNKs acts through SPAK to inhibit both transporters by controlling their surface expression. Remarkably, IRBIT completely inhibits these effects by antagonizing the function of SPAK. IRBIT does not prevent the interaction of SPAK with the transporters, but rather makes the transporters insensitive to SPAK. The molecular mechanism of how IRBIT prevents the effect of SPAK is being explored and will be reported.