Cyclosporine impairs the guanylyl cyclase activity of the natriuretic peptide receptor in the glomerulus

2000 ◽  
Vol 42 (5) ◽  
pp. 435-441 ◽  
Author(s):  
Hyun Kook ◽  
Soo W. Kim ◽  
Seon Y. Kang ◽  
Sung Z. Kim ◽  
Jae H. Kim ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Cyclase Activity ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Guanylyl Cyclase Activity

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

Hypertension ◽  
2004 ◽  
Vol 43 (2) ◽  
pp. 460-465 ◽  
Author(s):  
Thomas Langenickel ◽  
Jens Buttgereit ◽  
Ines Pagel ◽  
Rainer Dietz ◽  
Roland Willenbrock ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Site Directed Mutagenesis ◽  
Cyclase Activity ◽  
Directed Mutagenesis ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Guanylyl Cyclase Activity

scholarly journals Phosphorylation of the Kinase Homology Domain Is Essential for Activation of the A-Type Natriuretic Peptide Receptor

1998 ◽  
Vol 18 (4) ◽  
pp. 2164-2172 ◽  
Author(s):  
Lincoln R. Potter ◽  
Tony Hunter
Keyword(s):  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Receptor Activation ◽  
Dominant Negative ◽  
Cyclase Activity ◽  
Atp Binding ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Kinase Homology Domain ◽  
Kinase Homology

ABSTRACT Natriuretic peptide receptor A (NPR-A) is the biological receptor for atrial natriuretic peptide (ANP). Activation of the NPR-A guanylyl cyclase requires ANP binding to the extracellular domain and ATP binding to a putative site within its cytoplasmic region. The allosteric interaction of ATP with the intracellular kinase homology domain (KHD) is hypothesized to derepress the carboxyl-terminal guanylyl cyclase catalytic domain, resulting in the synthesis of the second messenger, cyclic GMP. Here, we show that phosphorylation of the KHD is essential for receptor activation. Using a combination of phosphopeptide mapping techniques, we have identified six residues within the ATP-binding domain (S497, T500, S502, S506, S510, and T513) which are phosphorylated when NPR-A is expressed in HEK 293 cells. Mutation of any one of these Ser or Thr residues to Ala caused reductions in the receptor phosphorylation state, the number and pattern of phosphopeptides observed in tryptic maps, and ANP-dependent guanylyl cyclase activity. The reductions were not explained by decreases in NPR-A protein levels, as indicated by immunoblot analysis and determinations of cyclase activity in the presence of detergent. Conversion of Ser-497 to Ala resulted in the most dramatic decrease in cyclase activity (∼20% of wild-type activity), but conversion to an acidic residue (Glu), which mimics the charge of the phosphoserine moiety, had no effect. Simultaneous mutation of five of the phosphorylation sites to Ala resulted in a dephosphorylated receptor which was unresponsive to hormone and had potent dominant negative inhibitory activity. We conclude that phosphorylation of the KHD is absolutely required for hormone-dependent activation of NPR-A.

scholarly journals Augmented Natriuretic Peptide-Induced Guanylyl Cyclase Activity and Vasodilation in Experimental Hyperglycemic Rats

2002 ◽  
Vol 88 (2) ◽  
pp. 167-173 ◽  
Author(s):  
Hyun Kook ◽  
JongUn Lee ◽  
Soo Wan Kim ◽  
Sang Woo Kim ◽  
Yung Hong Baik
Keyword(s):  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Cyclase Activity ◽  
Guanylyl Cyclase Activity

scholarly journals Molecular and genetic aspects of guanylyl cyclase natriuretic peptide receptor-A in regulation of blood pressure and renal function

2018 ◽  
Vol 50 (11) ◽  
pp. 913-928 ◽  
Author(s):  
Kailash N. Pandey
Keyword(s):  
Blood Pressure ◽  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Natriuretic Peptides ◽  
Molecular Mechanisms ◽  
Phenotypic Characterization ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Natriuretic Peptide Receptor A ◽  
Regulation Of Blood Pressure

Natriuretic peptides (NPs) exert diverse effects on several biological and physiological systems, such as kidney function, neural and endocrine signaling, energy metabolism, and cardiovascular function, playing pivotal roles in the regulation of blood pressure (BP) and cardiac and vascular homeostasis. NPs are collectively known as anti-hypertensive hormones and their main functions are directed toward eliciting natriuretic/diuretic, vasorelaxant, anti-proliferative, anti-inflammatory, and anti-hypertrophic effects, thereby, regulating the fluid volume, BP, and renal and cardiovascular conditions. Interactions of NPs with their cognate receptors display a central role in all aspects of cellular, biochemical, and molecular mechanisms that govern physiology and pathophysiology of BP and cardiovascular events. Among the NPs atrial and brain natriuretic peptides (ANP and BNP) activate guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) and initiate intracellular signaling. The genetic disruption of Npr1 (encoding GC-A/NPRA) in mice exhibits high BP and hypertensive heart disease that is seen in untreated hypertensive subjects, including high BP and heart failure. There has been a surge of interest in the NPs and their receptors and a wealth of information have emerged in the last four decades, including molecular structure, signaling mechanisms, altered phenotypic characterization of transgenic and gene-targeted animal models, and genetic analyses in humans. The major goal of the present review is to emphasize and summarize the critical findings and recent discoveries regarding the molecular and genetic regulation of NPs, physiological metabolic functions, and the signaling of receptor GC-A/NPRA with emphasis on the BP regulation and renal and cardiovascular disorders.

Conservation of the kinaselike regulatory domain is essential for activation of the natriuretic peptide receptor guanylyl cyclases

1992 ◽  
Vol 12 (6) ◽  
pp. 2581-2590
Author(s):  
K J Koller ◽  
F J de Sauvage ◽  
D G Lowe ◽  
D V Goeddel
Keyword(s):  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Cyclase Activity ◽  
Guanylyl Cyclases ◽  
Heat Stable ◽  
Guanylyl Cyclase Activity ◽  
Kinase Homology Domain ◽  
Kinase Homology

The natriuretic peptide receptors, NPR-A and NPR-B, are two members of the newly described class of receptor guanylyl cyclases. The kinaselike domain of these proteins is an important regulator of the guanylyl cyclase activity. To begin to understand the molecular nature of this type of regulation, we made complete and partial deletions of the kinase domain in NPR-A and NPR-B. We also made chimeric proteins in which the kinase domains of NPR-A and NPR-B were exchanged or replaced with kinase domains from structurally similar proteins. Complete deletion of the kinase homology domain in NPR-A and NPR-B resulted in constitutive activation of the guanylyl cyclase. Various partial deletions of this region produced proteins that had no ability to activate the enzyme with or without hormone stimulation. The kinase homology domain can be exchanged between the two subtypes with no effect on regulation. However, structurally similar kinaselike domains, such as from the epidermal growth factor receptor or from the heat-stable enterotoxin receptor, another member of the receptor guanylyl cyclase family, were not able to regulate the guanylyl cyclase activity correctly. These findings suggest that the kinaselike domain of NPR-A and NPR-B requires strict sequence conservation to maintain proper regulation of their guanylyl cyclase activity.

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