Natriuretic peptide receptor: structure and signaling.

The ANP receptor is a single-transmembrane sequence receptor coupled to guanylate cyclase (GCase). It belongs to a family of GCase-coupled receptors that share a common overall molecular configuration. Collectively, theses GCase-coupled receptors belong to a larger family of single-transmembrane sequence receptors that include growth hormone and cytokine receptors. The signal transduction mechanism of these receptors has not been thoroughly understood. Receptor dimerization (or oligomerization) has been suggested as the mechanism. However, at least for the ANP receptor, dimerization has been seen to occur in the absence of the ligand, suggesting that an additional, as yet unknown effect of hormone binding is responsible for receptor activation. To understand the signaling mechanism, some of the functions and subsites of the ANP receptor critical for signaling have been identified, including the binding stoichiometry, receptor self-association, the juxtamembrane hinge structure containing a signature motif critical for GCase signaling, ANP-binding site residues, chloride-dependence of ANP binding, disulfide linkages, and glycosylation structures. These structures and the functional sites have been identified in the crystal structure of dimerized recombinant extracellular domain of the ANP receptor. The intracellular domain contains a kinase-homologous domain that regulates the activity of the GCase domain responding to ANP binding and also to binding of the allosteric effector ATP. Moreover, this regulatory role of the kinase-homologous domain is modulated by its own phosphorylated state. Although considerable data have been accumulated, the mechanism of ANP receptor signaling has not been well defined. Further studies are necessary to understand how ANP binds to the receptor, what conformational effect is caused by ANP binding, how this effect is transduced across the cell membrane, and how this transmembrane effect leads to stimulation of the GCase catalytic activity.