Functional effects of nonsynonymous polymorphisms in the human TRPV1 gene.

Functional effects of nonsynonymous polymorphisms in the human TRPV1 gene. Research Abstract Details 

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Functional effects of nonsynonymous polymorphisms in the human TRPV1 gene. Abstract Text:

Hongshi Xu,Wei Tian,Yi Fu,Terry T Oyama,Sharon Anderson,David M Cohen,Hongshi Xu,Wei Tian,Yi Fu,Terry T Oyama,Sharon Anderson,David M Cohen,Hongshi Xu,Wei Tian,Yi Fu,Terry T Oyama,Sharon Anderson,David M Cohen,

The prototypical member of the vanilloid-responsive-like subfamily of transient receptor potential (TRP) channels is TRPV1. TRPV1 mediates aspects of nociception and neurogenic inflammation; however, new roles are emerging in sensation of both luminal stretch and systemic tonicity. Although at least six nonsynonymous polymorphisms in the human TRPV1 gene have been identified, there has been no systematic investigation into their functional consequences. When heterologously expressed in HEK293 cells, all variants exhibited equivalent EC(50) for the classic agonist capsaicin. This agonist elicited a greater maximal response in TRPV1(I315M) and TRPV1(P91S) variants (relative to TRPV1(WT)), as did a second agonist, anandamide. Expression of these two variants in whole-cell lysates and at the cell surface was markedly greater than that of wild-type TRPV1, whereas expression at the mRNA level was either unchanged (TRPV1(P91S)) or only very modestly increased (TRPV1(I315M)). Incorporation of multiple nonsynonymous SNPs, informed by the population-specific haplotype block structure of the TRPV1 gene, did not lead to variant channels with unique features vis-à-vis capsaicin responsiveness. Recently, polymorphisms/mutations were identified in two highly conserved TRPV1 residues in the nonobese diabetic (NOD) murine model. Incorporation of these changes into human TRPV1 gave rise to a channel with a normal EC(50) for capsaicin, but with a markedly elevated Hill slope such that the variant channel was hyporesponsive to capsaicin at low doses (<10 nM) and hyperresponsive at high doses (>10 nM). In aggregate, these data underscore expression-level and functional differences among naturally occurring TRPV1 variants; the implications with respect to human physiology are considered.

Functional effects of nonsynonymous polymorphisms in the human TRPV1 gene. Publishing Authors By Initials

H Xu,W Tian,Y Fu,TT Oyama,S Anderson,DM Cohen,H Xu,W Tian,Y Fu,TT Oyama,S Anderson,DM Cohen,H Xu,W Tian,Y Fu,TT Oyama,S Anderson,DM Cohen,

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Functional effects of nonsynonymous polymorphisms in the human TRPV1 gene. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: American journal of physiology. Renal physiology

VOLUME: 293

Page Numbers: F1865-76

Journal Abbreviation: Am. J. Physiol. Renal Physiol.

ISSN: 0363-6127

DAY: 3

MONTH: 10

YEAR: 2007

Functional effects of nonsynonymous polymorphisms in the human TRPV1 gene. Information

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LANGUAGE: eng

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AFFILIATION: Mailcode PP262, Oregon Health and Science University, 3314 S.W. US Veterans Hospital Rd., Portland, OR 97201. cohend@ohsu.edu).

Country: United States

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MEDLINETA: Am J Physiol Renal Physiol

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