Ca2+ Modulation of ANF-RGC: New Signaling Paradigm Interlocked with Blood Pressure Regulation

ANF-RGC is the prototype receptor membrane guanylate cyclase that is both the receptor and the signal transducer of the most hypotensive hormones, ANF and BNP. It is a single-transmembrane protein. After binding these hormones at the extracellular domain, ANF-RGC at its intracellular domain signals the activation of the C-terminal catalytic module and accelerates the production of the second messenger, cyclic GMP, which controls blood pressure, cardiac vasculature, and fluid secretion. At present, this is the sole transduction mechanism and the physiological function of ANF-RGC. Through comprehensive studies involving biochemistry, immunohistochemistry, and blood pressure measurements in mice with targeted gene deletions, this study demonstrates a new signaling model of ANF-RGC that also controls blood pressure. In this model, (1) ANF-RGC is not the transducer of ANF and BNP, (2) its extracellular domain is not used for signaling, and (3) the signal flow is not downstream from the extracellular domain to the core catalytic domain. Instead, the signal is the intracellular Ca2+, which is translated at the site of its reception, at the core catalytic domain of ANF-RGC. A model for this Ca2+ signal transduction is diagrammed. It captures Ca2+ through its Ca2+ sensor myristoylated neurocalcin 6 and upregulates ANF-RGC activity with a K-1/2 of 0.5 mu M. The neurocalcin delta-modulated domain resides in the (849)DIVGFTALSAESTPMQVV(866) segment of ANF-RGC, which is a part of the core catalytic domain. Thereby, ANF-RGC is primed to receive, transmit, and translate the Ca2+ signals into the generation of cyclic GMP at a rapid rate. The study defines a new paradigm of membrane guanylate cyclase signaling, which is linked to the physiology of cardiac vasculature regulation and possibly also to fluid secretion.