Structure, signaling mechanism and regulation of the natriuretic peptide receptor guanylate cyclase

Abstract

Summary Atrial natriuretic peptide (ANP) and homologous B-type natriuretic peptide (BNP) are cardiac hormones that dilate blood vessels and stimulate natriuresis and diuresis, thereby lowering blood pressure and blood volume. ANP and BNP counterbalance the actions of the renin-angiotensin-aldosterone and neurohormonal systems, and play a central role in cardiovascular regulation. These activities are mediated by the A-type natriuretic peptide receptor (NPRA), a single transmembrane segment, guanylate cyclase (GC) linked receptor that occurs as a homodimer. Here we present an overview of the structure, possible chloride-mediated regulation, and signaling mechanism of the NPRA and other receptor-GCs. Earlier, we determined the crystal structures of the NPRA extracellular domain with and without bound ANP. Their structural comparison has revealed a novel ANP-induced rotation mechanism occurring in the juxtamembrane region that apparently triggers transmembrane signal transduction. More recently, the crystal structures of the dimerized catalytic domain of green algae GC Cyg12 and that of cyanobacter GC Cya2 have been reported. These structures closely resemble that of the adenylate cyclase catalytic domain consisting of C1 and C2 subdomain heterodimer. AC is activated by binding of Gsα to C2 and ensuing 7° rotation of C1 around an axis parallel to the central cleft, thereby inducing the heterodimer into a catalytically active conformation. We speculate that, in the NPRA, the ANP-induced rotation of the juxtamembrane domains, transmitted across the transmembrane helices, may induce a similar rotation in each of the dimerized GC catalytic domains, leading to the stimulation of the GC catalytic activity.

Chloride is an Agonist of Group II and III Metabotropic Glutamate Receptors

“…Interestingly, the chloride binding site at group II and III mGlu receptors is structurally conserved at ANP receptors (Acher et al, 2011;Misono et al, 2011). While chloride is not an agonist of ANP receptors, chloride has been shown to modulate ANP receptor oligimerization (Ogawa et al, 2010).…”

“…For example, the kainate receptors require a chloride ion between protomers to facilitate dimerization (Chaudhry et al, 2009). It has also been shown that the binding of atrial natriuretic peptide (ANP) to ANP receptors requires chloride (Misono et al, 2011), and that the presence of chloride influences ANP receptor oligimerization (Ogawa et al, 2010). Interestingly, it has been reported that the ANP receptor chloride binding site is structurally conserved at mGlu receptors (Ogawa et al, 2010;Acher et al, 2011).…”

Spinal Functions of B-Type Natriuretic Peptide, Gastrin-Releasing Peptide, and Their Cognate Receptors for Regulating Itch in Mice

“…Natriuretic peptides are secreted by the ventricles of the heart, and they have been established as diagnostic and prognostic tools for cardiovascular diseases (Levin et al, 1998;Potter et al, 2009). B-type natriuretic peptide (BNP), originally isolated from porcine brain, binds to transmembrane natriuretic peptide receptor A (NPRA) (Mukoyama et al, 1991;Misono et al, 2011). A recent study reported that BNP-NPRA signaling is a key mechanism of itch transmission in the mouse spinal cord (Mishra and Hoon, 2013).…”

The Endocrinological Responses of Veno-Venous Extracorporeal Membrane Oxygenation on Hypoxic Fetal Lambs

“…It is now well established that ANP plays a major role in cardiovascular regulation through their natriuretic, diuretic, and vasorelaxant activities, as well as the end -organ activities that suppress cardiac hypertrophy and fibrosis and cardiomyocyte apoptosis 16) . In fetuses, levels of ANP are higher than in adults 17) .…”