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A Gain-of-Function SNP in TRPC4 Cation Channel Protects Against Myocardial Infarction.
MedLine Citation:
PMID:  21427121     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
AIMS The TRPC4 nonselective cation channel is widely expressed in the endothelium, where it generates Ca(2+) signals that participate in the endothelium-mediated vasodilatatory response. This study sought to identify single-nucleotide polymorphisms (SNPs) in the TRPC4 that are associated with myocardial infarction. METHODS AND RESULTS Our candidate-gene association studies identified a missense SNP (TRPC4-I957V) associated with reduced risk of myocardial infarction in diabetic patients (OR= 0.61; CI, 0.40-0.95, P=0.02). TRPC4 was also associated with myocardial infarction in the Wellcome Trust Case-Control Consortium's genome-wide data: an intronic SNP (rs7319926) within the same linkage disequilibrium block as TRPC4-I957V showed an OR of 0.86 (CI, 0.81-0.94; P=10(-4)). Functional studies of the missense SNP were carried out in HEK293 and CHO cells expressing wild type or mutant channels. Patch-clamp studies and measurement of intracellular [Ca(2+)] in response to muscarinic agonists and direct G-protein activation showed increased channel activity in TRPC4-I957V transfected cells, compared to TRPC4-WT. Site-directed mutagenesis and molecular modeling of TRPC4-I957V suggested that the gain of function was due to the presence of a less bulky Val-957. This permits a firmer interaction between the TRPC4 and the catalytic site of the tyrosine kinase that phosphorylates TRPC4 at Tyr-959 and facilitates channel insertion into the plasma membrane. CONCLUSIONS We provide evidence for the association of a TRPC4 SNP with myocardial infarction in population-based genetic studies. The higher Ca(2+) signals generated by TRPC4-I957V may ultimately facilitate the generation of endothelium- and nitric oxide-dependent vasorelaxation, thereby explaining its protective effect at the vasculature.
Authors:
Carole Jung; Gemma G Gené; Marta Tomas; Cristina Plata; Jana Selent; Manuel Pastor; César Fandos; Mariano Senti; Gavin Lucas; Roberto Elosua; Miguel A Valverde
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-3-22
Journal Detail:
Title:  Cardiovascular research     Volume:  -     ISSN:  1755-3245     ISO Abbreviation:  -     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-3-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Laboratory of Molecular Physiology and Channelopathies, Universitat Pompeu Fabra, Barcelona, Spain.
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