Forced Homodimerization by Site-Directed Mutagenesis Alters Guanylyl Cyclase Activity of Natriuretic Peptide Receptor B

Langenickel, Thomas; Buttgereit, Jens; Pagel, Ines; Dietz, Rainer; Willenbrock, Roland; Bäder, Michael

doi:10.1161/01.hyp.0000110907.33263.0b

Cited by 14 publications

(12 citation statements)

References 24 publications

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“…Langenickel et al 24 aimed to determine which residues of the extracellular ligand binding domain of natriuretic peptide receptors were important for dimerization and therefore cGMP induction. Both GC-A and GC-B receptors have an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain which in turn consists of a kinase homology domain, a hinge region, and a guanylyl cyclase domain.…”

Section: Gc-b Receptormentioning

confidence: 99%

Natriuretic Peptides

Richards

2007

Hypertension

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In the 25 years since de Bold et al demonstrated the existence of an atrial natriuretic factor, investigation of the cardiac natriuretic peptides has produced a maturing knowledge base 1,2 identifying the cardiac peptides and addressing stimuli for secretion of atrial (ANP) and B-type (BNP) natriuretic peptides, the processing and release of the mature bioactive carboxy terminal peptides, together with their propeptides and amino terminal fragments, the nature of natriuretic peptide receptors, and the bioactivities of natriuretic peptides (including natriuresis, vasodilatation, suppression of renin-angiotensin-aldosterone and sympathetic nervous activity, and trophic effects inhibiting vascular and cardiac hypertrophy and fibrosis). Less is known of the more recently discovered C-type natriuretic peptide (CNP and its cosecreted amino-terminal peptide, NTproCNP). 3,4 Increasingly, measurements of the B-type peptides have found diagnostic and prognostic application in cardiovascular disease. [5][6][7] The genes for ANP and BNP are in tandem on human chromosome 1. 8 Upstream regulatory regions identified for the BNP gene include an AP1 binding site, serum response elements, M-CAT and GATA sites. 9,10 Translation results in pre-pro BNP from which a 26 amino acid signal peptide is cleaved to produce the 108 amino acid precursor proBNP. This in turn is processed between amino acid residues 76 and 77 resulting in a 32 amino acid biologically active peptide (BNP) from its carboxy terminal plus the remaining amino terminal peptide sequence (NTproBNP 1 to 76). ANP is synthesized as a 126 amino acid precursor and is stored in granules within atrial tissue. 11 During or shortly after secretion, the precursor is processed to an active 28 amino acid carboxy terminal peptide (ANP) and amino terminal ANP (proANP 1 to 98). The amino terminal propeptides NTproANP, NTproBNP, and NTproCNP have no known biological actions. The mature bioactive human forms of ANP, BNP, and CNP all contain a 17 member amino acid ring bound by cysteine-to-cysteine disulphide bonds with 11 of the 16 residues being conserved across ANP, BNP, and CNP. The 3 peptides have varying length amino terminal and carboxy terminal amino acid residue "tails" with CNP essentially lacking any carboxy terminal extension beyond the ring structure. The actions of ANP and BNP are mediated predominantly via the GC-A receptor and those of CNP via the GC-B receptor. All 3 peptides are subject to varying degrees of degradation by neutral endopeptidase (EC 3.4.24.11) and via uptake by the C ("clearance") receptor.ANP and BNP and their receptors are widely distributed in brain, spinal cord, pituitary, kidney, adrenal gland, and vasculature in addition to the heart. Concentrations of immunoreactive ANP and BNP within the heart are up to 3 orders of magnitude higher than elsewhere, and within cardiac atria the concentrations of both peptides are 1 to 2 orders of magnitude higher than in ventricle. 12 CNP is also widely distributed mainly in the vasculature with far lower cardiac ...

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Section: Gc-b Receptormentioning

confidence: 99%

Natriuretic Peptides

Richards

2007

Hypertension

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“…The accumulation of cGMP upon ligand stimulation requires a dimerization of receptor molecules including the cytoplasmatic kinase homology domain. This process leads to a tight contact of two guanylyl cyclase domains resulting in conversion of Mg 2ϩ -GTP to 3Ј,5Ј-cGMP (5,6).…”

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confidence: 99%

Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B

Langenickel

Buttgereit

Pagel-Langenickel

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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116

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Natriuretic peptides (NP) mediate their effects by activating membrane-bound guanylyl cyclase-coupled receptors A (NPR-A) or B (NPR-B). Whereas the pathophysiological role of NPR-A has been widely studied, only limited knowledge on the cardiovascular function of NPR-B is available. In vitro studies suggest antiproliferative and antihypertrophic actions of the NPR-B ligand C-type NP (CNP). Because of the lack of a specific pharmacological inhibitor, these effects could not clearly be attributed to impaired NPR-B signaling. Recently, gene deletion revealed a predominant role of NPR-B in endochondral ossification and development of female reproductive organs. However, morphological abnormalities and premature death of NPR-B-deficient mice preclude detailed cardiovascular phenotyping. In the present study, a dominant-negative mutant (NPR-B⌬KC) was used to characterize CNP-dependent NPR-B signaling in vitro and in transgenic rats. Here we demonstrate that reduced CNP-but not atrial NP-dependent cGMP response attenuates antihypertrophic potency of CNP in vitro. In transgenic rats, NPR-B⌬KC expression selectively reduced NPR-B but not NPR-A signaling. NPR-B⌬KC transgenic rats display progressive, blood pressure-independent cardiac hypertrophy and elevated heart rate. The hypertrophic phenotype is further enhanced in chronic volume overload-induced congestive heart failure. Thus, this study provides evidence linking NPR-B signaling to the control of cardiac growth.C-type natriuretic peptide ͉ knockdown

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“…1B, E) and NPR-B as confirmed by RT-PCR and enzyme activity studies [17,23]. Cells were transfected with pEGFP-VILIP-1 or the empty vector (mock) and the expression was confirmed by the detection of the EGFP fluorescence ( Fig.…”

Section: Vilip-1 Regulates Npr-b Membrane Association In Vitromentioning

confidence: 86%

“…The reaction was stopped by placing culture dishes on ice and disrupting the cells by sonication. Determination of cGMP concentration was done by radioimmunoassay as described previously [23]. …”

Section: Stimulation and Determination Of Intracellular Cgmp Productionmentioning

confidence: 99%

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Visinin-like protein 1 regulates natriuretic peptide receptor B in the heart

Buttgereit

Qadri

Monti

et al. 2010

Regulatory Peptides

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Accumulating evidence indicates that Visinin-like protein-1 (VILIP-1), a member of the family of neuronal calcium sensor proteins (NCS), modulates a variety of processes in extra-neuronal tissues. In this study, we describe VILIP-1 expression in the human heart, rat cardiomyocytes, and H9c2 cells, and demonstrate that VILIP-1 regulates the cell surface localization of natriuretic peptide receptor B (NPR-B). In preparations from failing hearts, we observed VILIP-1 downregulation and reduced NPR-B signalling. In conclusion, VILIP-1 deficiency may be responsible for the reduced efficiency of the natriuretic peptide system in cardiac hypertrophy and heart failure and may therefore serve as pharmacological target.3

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Forced Homodimerization by Site-Directed Mutagenesis Alters Guanylyl Cyclase Activity of Natriuretic Peptide Receptor B

Cited by 14 publications

References 24 publications

Natriuretic Peptides

Natriuretic Peptides

Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B

Visinin-like protein 1 regulates natriuretic peptide receptor B in the heart

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