Discovery of an alternate mechanism for the inhibition of particulate guanylyl cyclases by the natriuretic peptide ‘clearance’ receptor

Abstract

AbstractThe 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 so-called ‘clearance’ receptor NPRC 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 a previously unknown mechanism by which NPRC interferes with the cGMP signaling function of the NPs: by forming a heterodimer with monomeric NPRA or NPRB, NPRC prevents the formation of a functional guanylyl cyclase domain and thereby suppressing cGMP production.Significance StatementNatriuretic peptides (NP) are hormones that are important regulators of vascular and cardiac function, in part via 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. Until now, it has been thought that inhibition of NP signaling by NPRC was achieved via competition for and degradation of NP ligands. Here, we demonstrate a new mechanism by which NPRC inhibits NP signaling: NPRC forms non-functional heterodimers with NPRA and NPRB thereby abrogating NP signaling. This finding establishes a novel mechanistic role for NPRC.