Function and Dysfunction of Mammalian Membrane Guanylyl Cyclase Receptors: Lessons from Genetic Mouse Models and Implications for Human Diseases

Abstract

Besides soluble guanylyl cyclase (GC), the receptor for NO, there are seven plasma membrane forms of guanylyl cyclase (GC) receptors, enzymes that synthesize the second-messenger cyclic GMP (cGMP). All membrane GCs (GC-A to GC-G) share a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic (GC) region. Although the presence of the extracellular domain suggests that all these enzymes function as receptors, specific ligands have been identified for only four of them (GC-A through GC-D). GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart. GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification. GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation. GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Finally, GC-D and GC-G appear to be pseudogenes in the human. In rodents, GC-D is exclusively expressed in the olfactory neuroepithelium, with chemosensory functions. GC-G is the last member of the membrane GC form to be identified. No other mammalian transmembrane GCs are predicted on the basis of gene sequence repositories. In contrast to the other orphan receptor GCs, GC-G has a broad tissue distribution in rodents, including the lung, intestine, kidney, skeletal muscle, and sperm, raising the possibility that there is another yet to be discovered family of cGMP-generating ligands. This chapter reviews the structure and functions of membrane GCs, with special focus on the insights gained to date from genetically modified mice and the role of alterations of these ligand/receptor systems in human diseases.

Intramyocardial BNP Gene Delivery Improves Cardiac Function Through Distinct Context-Dependent Mechanisms

“…GC-A is expressed in cardiac myocytes, fibroblasts, and endothelial cells in the heart. 30,31 Although marked species differences exist in the potency for cGMP production among BNPs and the potency of BNPs for cGMP production varies from cell to cell, 8,24,32 cGMP production has been reported to be activated by human BNP in rats cells, in agreement with our present results. For example, human BNP-32 added to purified rat ventricular myocytes resulted in a marked accumulation of cGMP, similar to rat ANP.…”

“…23,24 In cultured fibroblasts, BNP decreases collagen synthesis and increases matrix metalloproteinases (MMPs). 25 Accordingly, overexpression of BNP in mice, targeted to the liver, has been shown to increase MMP-9 expression in the infarcted region after MI.…”

Cyclic GMP signaling in rat urinary bladder, prostate, and epididymis: tissue-specific changes with aging and in response to Leydig cell depletion

“…Considering the well-established expression of membrane GC in epithelial (e.g. kidney and intestine) and endothelial cells and their impact for ion transport and permeability (Kuhn 2009, Sabbatini 2009), roles for GC-A and/or GC-B in modulating the luminal milieu along the epididymal duct are well conceivable. In apparent support and raising particular future attention to GC-B, CNP is strongly produced by epithelial cells of the epididymis (Nielsen et al 2008).…”

“…In most tissues, cellular accumulations of cGMP are induced by either natriuretic peptide (NP) membrane receptors with guanylyl cyclase (GC) activity (referred to as GC-A and GC-B) and/or the nontransmembrane protein soluble GC (sGC). GC-A (also known as NPR-A or NPR1) is activated by the cardiac hormones atrial NP (ANP, also known as NPPA) and B-type NP (also known as NPPB), whereas GC-B (NPR-B or NPR2) acts as specific receptor for a third peptide, C-type NP (CNP, also known as NPPC; Kuhn 2009). Stimulation of sGC is evoked by nitric oxide (NO) binding, and one important and widely distributed generator of NO is the enzyme endothelial NO synthase (NOS3, also known as eNOS; Alderton et al 2001).…”

In vivo genetic dissection of O2-evoked cGMP dynamics in aCaenorhabditis elegansgas sensor

“…Mammals have several families of GCs (14,15) and eight families of cGMP PDEs (16), each with distinct regulatory properties. Different PDE types are often coexpressed, but little is known about how they work together.…”