Receptors with guanylate cyclase activity

Nesiritide recombinant human B-type natriuretic peptide (rh BNP) used intravenously. The aid name was ANF. ANF receptors have guanylate cyclase activity, and nesiritide stimulation of die receptor T concentrations of cGMP, relaxing smooth muscles of veins and arteries. Nesiritide is used in decompensated CHF patients who have dyspnea at rest or with minimal... 

There are two major families of guanylate cyclase, the particulate-associated enzymes, which are actually transmembrane receptors that contain guanylate cyclase within their intracellular domains, and the soluble type activated by NO (Kimura and Murad, 1974 Kuno et al., 1986 Schulz et al., 1991 Garbers, 1992 Schmidt et al., 1993). With more details of the structure and function of these enzymes, however, this strict division may become blurred. For example, NO-stimulated guanylate cyclase activity has been found to be associated with the membrane fraction of cells in some cases (Murad, 1994). 

The mechanism of activation of the receptor-type guanylate cyclases is not entirely clear. As is the case with other single-transmembrane domain receptor types, such as receptor-type tyrosine kinases, some sort of dimerization may be induced by ligand binding, which serves to activate the intracellular enzyme part of the receptor. As discussed in the next section, dimerization is essential to enzyme activity in soluble guanylate cyclases. 

As yet, it has not been possible to pinpoint the exact site of injury to the L-arginine nitric oxide pathway. The defect may lie with the surface receptors, signal transduction, L-arginine deficiency, nitric oxide synthase, tolerance of smooth muscle, physical obstruction to the diffusion of nitric oxide by a thickened intima, or impaired guanylate cyclase activation. However, endogenous guanylate cyclase can be activated by exogenously administered nitric oxide to relax smooth muscle, even when unresponsive to acetyl-... 

Figure 4.12. Model for ANP-A and ANP-B receptor function. The unoccupied ANP-A receptor is shown on the left with a basal rate of cGMP synthesis (indicated by a thin arrow). The effect of ligand binding to the amino-terminal extracellular domain is shown on the right. Proposed allosteric modulation of guanylate cyclase by a-ANP is schematically illustrated by a change in shape of the intracellular domain and a thicker arrow to denote an increase in guanylate cyclase-specific activity with greater production of the second messenger cGMP.

Nesiritide is a human B-type natriuretic peptide, which binds to the particulate guanylate cyclase receptor of vascular smooth muscle and endothelial cells, leading to dose-dependent reductions in pulmonary capillary wedge pressure and systemic arterial pressure in patients with heart failure. It is indicated in the treatment of patients with acutely decompensated CHF who have dyspnea at rest or with minimal activity. 

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