Atrial natriuretic factor receptor guanylate cyclase, ANF-RGC, transduces two independent signals, ANF and Ca(2+)

Abstract

Atrial natriuretic factor receptor guanylate cyclase (ANF-RGC), was the first discovered member of the mammalian membrane guanylate cyclase family. The hallmark feature of the family is that a single protein contains both the site for recognition of the regulatory signal and the ability to transduce it into the production of the second messenger, cyclic GMP. For over two decades, the family has been classified into two subfamilies, the hormone receptor subfamily with ANF-RGC being its paramount member, and the Ca(2+) modulated subfamily, which includes the rod outer segment guanylate cyclases, ROS-GC1 and 2, and the olfactory neuroepithelial guanylate cyclase. ANF-RGC is the receptor and the signal transducer of the most hypotensive hormones, ANF- and B-type natriuretic peptide (BNP). After binding these hormones at the extracellular domain it, at its intracellular domain, signals activation of the C-terminal catalytic module and accelerates the production of cyclic GMP. Cyclic GMP then serves the second messenger role in biological responses of ANF and BNP such as natriuresis, diuresis, vasorelaxation, and anti-proliferation. Very recently another modus operandus for ANF-RGC was revealed. Its crux is that ANF-RGC activity is also regulated by Ca(2+). The Ca(2+) sensor neurocalcin d mediates this signaling mechanism. Strikingly, the Ca(2+) and ANF signaling mechanisms employ separate structural motifs of ANF-RGC in modulating its core catalytic domain in accelerating the production of cyclic GMP. In this review the biochemistry and physiology of these mechanisms with emphasis on cardiovascular regulation will be discussed.

Keywords: atrial natriuretic factor; atrial natriuretic factor receptor guanylate cyclase; calcium; cyclic GMP; neurocalcin δ; signal transduction.

FIGURE 1

ATP binding to the ARM domain affects the conformation of the six phosphorylable residues. The conformation of the six phosphorylated residues is shown before (cyan) and after (red) ATP binding. The ATP molecule is shown in green. The positions of the OH groups are indicated by cyan and red balls (reproduced with permission from ref. Duda et al., 2011).

FIGURE 2

(A) Amino acid residues surrounding W⁶⁰¹ and (B) amino acid residues surrounding W⁶⁶⁹ within the ARM domain. Amino acid residues depicted in red are located within a 4 Å sphere from the respective tryptophan residue (green). (C) Conformational changes within the ⁶⁶⁹WTAPELL⁶⁷⁵ motif induced by ATP binding to the ARM domain. The backbone structure of the ATP-bound ARM domain is shown in cyan and the ATP molecule is in green. The ⁶⁶⁹WTAPELL⁶⁷⁵ motif is shown in magenta color. Apo structure of the ARM domain was superimposed on the ATP-bound form to assess the relative, ATP binding induced, conformational changes. For clarity, only the ⁶⁶⁹WTAPELL⁶⁷⁵ motif (shown in red) of the apo-enzyme is visible. ATP binding results in a more compact structure of the ARM domain: the W⁶⁶⁹ side chain moves toward the ATP binding pocket while the side chains of T⁶⁷⁰, E⁶⁷³, L⁶⁷⁴, and L⁶⁷⁵ move toward the protein surface [compare the orientation of side chain of these amino acid residues before (in red) and after (in magenta) ATP binding; fonts for W⁶⁶⁹ and L⁶⁷⁵ residues are increased for better visibility]. This movement changes the surface properties of the ARM domain. The movement toward the surface of the protein is poised to facilitate interaction of this amino acid stretch with subsequent transduction motif, possibly within the catalytic domain, propagation of the ANF/ATP binding signal and activation of the catalytic domain (reproduced with permission from ref. Duda et al., 2009).

FIGURE 3

(A) Topography of ANF-RGC. The dashed lines on the right show the boundaries of: LS, leader sequence; ExtD, extracellular domain; TM, transmembrane domain; ICD, intracellular domain. The functional domains in ICD, their names and the aa constituting their boundaries are indicated at the left: JMD, juxtamembrane domain; ARM, the ATP regulated module; SHD-signaling helix domain; CCD-core catalytic domain. The site targeted by NCδ (encircled) is within CCD. (B) The signaling pathways of ANF and of NCδ are independent. The trajectory of the ANF pathway is in red dashed arrow. From the ExtD, it passes through the TM, ARM and SHD in its course to CCD. The trajectory of the NCδ pathway (in blue dashed arrow) is within the CCD. The CCD exists as an antiparallel homodimer (reproduced with permission from ref. Duda et al., 2012b).