Biochemistry and physiology of the natriuretic peptide receptor guanylyl cyclases

Tremblay, Johanne; Desjardins, Richard; Hum, David; Gutkowska, Jolanta; Hamet, Pavel

doi:10.1007/978-1-4615-0927-1_2

Cited by 40 publications

(49 citation statements)

References 165 publications

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“…102 Functional analysis of the GC-A gene promoter revealed a putative cGMP-responsive element, suggesting that the ANP-dependent downregulation of GC-A mRNA is cGMP dependent. 103,104 However, other studies could not reproduce this result. 105 Two recent in vitro studies have indicated that GC-A gene transcription might be inhibited by Ang II and endothelin.…”

Section: Regulation Of Gc-a At the Level Of Gene Transcriptionmentioning

confidence: 86%

Structure, Regulation, and Function of Mammalian Membrane Guanylyl Cyclase Receptors, With a Focus on Guanylyl Cyclase-A

Kühn

2003

Circulation Research

241

161

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Abstract-Besides soluble guanylyl cyclase (GC), the receptor for NO, there are at least seven plasma membrane enzymes that synthesize the second-messenger cGMP. All membrane GCs (GC-A through 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 three of them (GC-A through GC-C). GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic actions in the heart. GC-B is a specific receptor for C-type natriuretic peptide, having more of a paracrine function in vascular regeneration and endochondral ossification. GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and on 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, the functions of GC-D (located in the olfactory neuroepithelium) and GC-G (expressed in highest amounts in lung, intestine, and skeletal muscle) are completely unknown. This review discusses the structure and functions of membrane GCs, with special emphasis on the physiological endocrine and cardiac functions of GC-A, the regulation of hormone-dependent GC-A activity, and the relevance of alterations of the atrial natriuretic peptide/GC-A system to cardiovascular diseases. (Circ Res. 2003;93:700-709.)

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Section: Regulation Of Gc-a At the Level Of Gene Transcriptionmentioning

confidence: 86%

Structure, Regulation, and Function of Mammalian Membrane Guanylyl Cyclase Receptors, With a Focus on Guanylyl Cyclase-A

Kühn

2003

Circulation Research

241

161

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“…Thus, preincubation of A10 smooth muscle cells or NIH 3T3 fibroblasts for 18 hours with 10 or 100 nM ANP induced a 45% reduction of ANP-stimulated guanylyl cyclase activity (PϽ0.05). 1 To study Npr1 gene promoter activity and its regulation by its ligand ANP, we submitted a Ϫ1520 to 0 fragment of the Npr1 promoter to serial, directed deletions with exonuclease III. P values calculated by ANOVA compared the efficiency of nonlabeled probes to displace the P6-labeled probe.…”

Section: Identification Of An Anp/cgmp Cis-responsive Elementmentioning

confidence: 99%

Characterization of a cGMP-Response Element in the Guanylyl Cyclase/Natriuretic Peptide Receptor A Gene Promoter

et al. 2004

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Abstract-Previous studies have shown that atrial natriuretic peptide (ANP) can inhibit transcription of its receptor, guanylyl cyclase A, by a mechanism dependent on cGMP and have suggested the presence of a putative cGMP-response element (cGMP-RE) in the Npr1 gene promoter. To localize and characterize the putative cis-acting element, we have subcloned a 1520-bp fragment of the rat Npr1 promoter in an expression vector containing the luciferase reporter gene. Several fragments, generated by exonuclease III-directed deletions, were transiently transfected into cells to measure their promoter activity. Deletion from Ϫ1520 to Ϫ1396 of a 1520-bp-long Npr1 promoter led to a 5-fold increase in luciferase activity. Subsequent deletion to the position Ϫ1307 resulted in a decrease of luciferase activity by 90%. Preincubation of cells with 100 nM of ANP or 100 M 8-bromo-cGMP inhibited luciferase activity of the 1520-bp and 1396-bp-long fragments, but not the activity of the 1307-bp fragment, suggesting that the cGMP-RE is localized between positions Ϫ1396 and Ϫ1307. The cGMP regulatory region was narrowed by gel shift assays and footprinting to position Ϫ1372 to Ϫ1354 from the transcription start site of Npr1 and indicated its interaction with transcriptional factor(s). Cross-competition experiments with mutated oligonucleotides led to the definition of a consensus sequence (Ϫ1372 AaAtRKaNTTCaAcAKTY Ϫ1354) for the novel cGMP-RE, which is conserved in the human (75% identity) and mouse (95% identity) Npr1 promoters. Key Words: cyclic GMP Ⅲ natriuretic peptides Ⅲ receptors, atrial natriuretic factor A trial natriuretic peptide (ANP) is a cardiac hormone with potent effects in the kidney, vasculature, and nervous system. It has vasorelaxant activity in vascular smooth muscle and promotes urinary sodium and water excretion by the kidney (for review, see Reference 1 ). These actions of ANP are brought about via the activation of membrane-bound protein, natriuretic peptide receptor type A (NPR-A), or guanylyl cyclase A. 2-4 NPR-A is a 130-KDa transmembrane protein containing an ANP-binding motif at its extracellular NH 2 terminus and GC activity at its COOH-terminal intracellular domain. 5 Activation of NPR-A leads to the conversion of GTP to the intracellular second messenger cGMP, which is involved in most of the biological responses associated with natriuretic peptides. 2-5 Increased cGMP yields receptor desensitization, resulting in a decrease of ANP-stimulated cGMP synthesis. 6 Receptor preoccupancy appears to be a mechanism of apparent receptor desensitization 7 but transfection experiments with NPR-A cDNA have revealed that early desensitization by ANP pretreatment can be due to dephosphorylation of NPR-A protein. 8 Besides, a previous study demonstrated that NPR-A activity, as well as its mRNA levels, is diminished in a time-and concentration-dependent manner by ANP or by a cell-permeable cGMP analog, 8-bromo-cGMP. 9 Those results suggest transcriptional regulation via a putative cGMPresponse element (cGMP-RE) in the p...

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“…CNP signals in a paracrine fashion to stimulate vasorelaxation and long bone growth. The known effects of natriuretic peptides are mediated through the two cell-surface guanylyl cyclase receptors (Schulz and Waldman, 1999;Potter and Hunter, 2001;Silberbach and Roberts, 2001;Misono, 2002;Tremblay et al, 2002). NPR-A, also known as GC-A, is selectively activated by ANP and brain natriuretic peptide, whereas NPR-B, also known as GC-B, is activated by CNP.…”

Section: Introductionmentioning

confidence: 99%

Down-Regulation Does Not Mediate Natriuretic Peptide-Dependent Desensitization of Natriuretic Peptide Receptor (NPR)-A or NPR-B: Guanylyl Cyclase-Linked Natriuretic Peptide Receptors Do Not Internalize

et al. 2004

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Natriuretic peptide receptor A (NPR-A/GC-A) and B (NPR-B/ GC-B) are members of the transmembrane guanylyl cyclase family that mediate the effects of natriuretic peptides via the second messenger, cGMP. Despite numerous reports of these receptors being down-regulated in response to various pathological conditions, no studies have actually measured desensitization and receptor internalization in the same cell line. Furthermore, the ligand-dependent trafficking properties of NPR-A remain controversial, whereas nothing is known about the trafficking of NPR-B. In this report, we tested whether downregulation explains the ligand-dependent desensitization of NPR-A and NPR-B and characterized their trafficking properties using a combination of hormone-binding and antibodybased assays. Quantitative partition analysis indicated that 125 I-atrial natriuretic peptide (ANP) was rapidly released into the medium after 293T cells stably expressing NPR-A were warmed from 4°to 37°C. High-performance liquid chromatography fractionation of medium supplemented with the protease inhibitor phosphoramidon indicated that the 125 I-ANP was mostly intact. In contrast, 125 I-ANP purified from medium bathing cells expressing NPR-C, a receptor known to internalize natriuretic peptides, was degraded. Cleavable biotinylation and noncleavable biotinylation assays indicated that neither NPR-A nor NPR-B was internalized or degraded in response to natriuretic peptide binding. In contrast, agonist-dependent internalization of a G protein-coupled receptor was clearly apparent in the same cell line. Finally, we show that NPR-A and NPR-B are desensitized in cells in which they are not internalized. We suggest that mechanisms other than receptor down-regulation account for the desensitization of NPR-A and NPR-B that occurs in response to various physiological and pathological stimuli.Atrial natriuretic peptide (ANP), brain natriuretic peptide, and C-type natriuretic peptide (CNP) comprise the mammalian natriuretic peptide family (Levin et al., 1998). ANP and brain natriuretic peptide are endocrine cardiac hormones that decrease blood pressure through the stimulation of renal sodium and water excretion, vasorelaxation, and antagonization of the renin-angiotensin-aldosterone system. CNP signals in a paracrine fashion to stimulate vasorelaxation and long bone growth. The known effects of natriuretic peptides are mediated through the two cell-surface guanylyl cyclase receptors (Schulz and Waldman, 1999;Potter and Hunter, 2001;Silberbach and Roberts, 2001;Misono, 2002;Tremblay et al., 2002). NPR-A, also known as GC-A, is selectively activated by ANP and brain natriuretic peptide, whereas NPR-B, also known as GC-B, is activated by CNP. Both receptors consist of an extracellular ligand-binding domain, a single membrane-spanning region, and intracellular kinase homology, dimerization, and carboxyl-terminal guanylyl cyclase domains. In addition, all three natriuretic peptides bind a third protein called the natriuretic peptide clearance receptor (NPR-C)...

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Biochemistry and physiology of the natriuretic peptide receptor guanylyl cyclases

Cited by 40 publications

References 165 publications

Structure, Regulation, and Function of Mammalian Membrane Guanylyl Cyclase Receptors, With a Focus on Guanylyl Cyclase-A

Structure, Regulation, and Function of Mammalian Membrane Guanylyl Cyclase Receptors, With a Focus on Guanylyl Cyclase-A

Characterization of a cGMP-Response Element in the Guanylyl Cyclase/Natriuretic Peptide Receptor A Gene Promoter

Down-Regulation Does Not Mediate Natriuretic Peptide-Dependent Desensitization of Natriuretic Peptide Receptor (NPR)-A or NPR-B: Guanylyl Cyclase-Linked Natriuretic Peptide Receptors Do Not Internalize

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