Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ventricular myocytes are known to show increased expression of the cardiac hormones atrial and brain natriuretic peptide (ANP and BNP, respectively) in response to pathological stress on the heart, but their function during the progression of nonischemic dilated cardiomyopathy remains unclear. In this study, we crossed a mouse model of dilated cardiomyopathy and sudden death, which we generated by cardioselectively overexpressing a dominant-negative form of the transcriptional repressor neuron-restrictive silencer factor (dnNRSF Tg mice), with mice lacking guanylyl cyclase-A (GC-A), a common receptor for ANP and BNP, to assess the effects of endogenously expressed natriuretic peptides during progression of the cardiomyopathy seen in dnNRSF Tg mice. We found that dnNRSF Tg;GC-A(-/-) mice were born normally, but then most died within 4 wk. The survival rates among dnNRSF Tg;GC-A(+/-) and dnNRSF Tg mice were comparable, but dnNRSF Tg;GC-A(+/-) mice showed greater systolic dysfunction and a more severe cardiomyopathic phenotype than dnNRSF Tg mice. Collectively, our findings suggest that endogenous ANP/BNP protects the heart against the death and progression of pathological remodeling in a mouse model of dilated cardiomyopathy and sudden death.
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PMID:Endogenous cardiac natriuretic peptides protect the heart in a mouse model of dilated cardiomyopathy and sudden death. 1934 56

NPR1/GCA (natriuretic peptide receptor 1/guanylyl cyclase A) expression is controlled by several agents, including ANP (atrial natriuretic peptide). After ANP stimulation, NPR1/GCA down-regulates the transcriptional activity of its gene via a cGMP-dependent mechanism. Because we previously identified a cis-acting element responsible for this cGMP sensitivity, we proceed here to explore novel putative protein binding to cGMP-response element (cGMP-RE). Using the yeast one-hybrid technique with a human kidney cDNA library, we identified a strong positive clone able to bind cGMP-RE. The clone was derived from 1083-bp-long cDNA of a gene of yet unknown function localized on human chromosome 1 (1p33.36). We named this new protein GREBP (for cGMP-response element-binding protein). DNA binding assays showed 18-fold higher cGMP-RE binding capacity than the controls, whereas an electromobility shift assay indicated a specific binding for the cGMP-RE, and chromatin immunoprecipitation confirmed the binding of GREBP to the element under physiological conditions. By acting on cGMP-RE, GREBP inhibited the expression of a luciferase-coupled NPR1 promoter construct. In H295R cells, ANP heightened GREBP expression by 60% after just 3 h of treatment while inhibiting NPR1/GCA expression by 30%. Silencing GREBP with specific small interfering RNA increased the activity of the luciferase-coupled NPR1 promoter and GCA/NPR1 mRNA levels. GREBP is a nuclear protein mainly expressed in the heart. We report here the existence of a human-specific gene that acts as a transcriptional repressor of the NPR1/GCA gene.
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PMID:GREBP, a cGMP-response element-binding protein repressing the transcription of natriuretic peptide receptor 1 (NPR1/GCA). 2044 5

Neuronal calcium sensor (NCS) proteins, a sub-branch of the EF-hand superfamily, are expressed in the brain and retina where they transduce calcium signals and are genetically linked to degenerative diseases. The amino acid sequences of NCS proteins are highly conserved but their physiological functions are quite distinct. Retinal recoverin and guanylate cyclase activating proteins (GCAPs) both serve as calcium sensors in retinal rod cells, neuronal frequenin (NCS1) modulates synaptic activity and neuronal secretion, K(+) channel interacting proteins (KChIPs) regulate ion channels to control neuronal excitability, and DREAM (KChIP3) is a transcriptional repressor that regulates neuronal gene expression. Here we review the molecular structures of myristoylated forms of NCS1, recoverin, and GCAP1 that all look very different, suggesting that the sequestered myristoyl group helps to refold these highly homologous proteins into very different structures. The molecular structure of NCS target complexes have been solved for recoverin bound to rhodopsin kinase (RK), NCS-1 bound to phosphatidylinositol 4-kinase, and KChIP1 bound to A-type K(+) channels. We propose that N-terminal myristoylation is critical for shaping each NCS family member into a different structure, which upon Ca(2+)-induced extrusion of the myristoyl group exposes a unique set of previously masked residues that interact with a particular physiological target.
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PMID:Molecular structure and target recognition of neuronal calcium sensor proteins. 2724 27