Discovery of an alternate mechanism for the inhibition of particulate guanylyl cyclases by the natriuretic peptide 'clearance' receptor
The cardiac natriuretic peptides (NPs) control pivotal physiological actions such as fluid and electrolyte balance, cardiovascular homeostasis, and adipose tissue metabolism by activating their receptor enzymes (NPRA and NPRB). These receptors are homodimers that generate intracellular cyclic guanosine monophosphate (cGMP). The NP receptor NPRC, nicknamed the clearance receptor, lacks a guanylyl cyclase domain; instead, it can bind the NPs to internalize and degrade them. The conventional paradigm is that by competing for and internalizing NPs, NPRC blunts the ability of NPs to signal through NPRA and NPRB. Here we show another previously unknown mechanism by which NPRC can interfere with the cGMP signaling function of the NP receptors. By forming a heterodimer with monomeric NPRA or NPRB, NPRC can prevent the formation of a functional guanylyl cyclase domain and thereby suppress cGMP production in a cell-autonomous manner. Significance StatementNatriuretic peptides (NP) are hormones that are established regulators of vascular and cardiac function, in part through their regulation of fluid and electrolyte balance. NPs signal through particulate guanylyl cyclases (NPRA and NPRB), which are homodimeric membrane-bound receptor enzymes that generate cGMP upon NP binding. Additionally, a silent NP receptor (NPRC) lacks the guanylyl cyclase domain and is a negative regulator of NP signaling. It has been demonstrated that NPRC undergoes internalization and recycling and thus removes NPs, thereby blunting activation of the guanylyl cyclase-containing receptors. Here we show an additional mechanism by which NPRC inhibits NP signaling. Our results show that NPRC can directly interact with NPRA and NPRB, forming non-functional receptor heterodimers with NPRA and NPRB, thereby abrogating NP-evoked cGMP production. This finding establishes another novel mechanistic role for NPRC.