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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/F1865    most recent 00347.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Xu, H. Articles by Cohen, D. M. Search for Related Content PubMed PubMed Citation Articles by Xu, H. Articles by Cohen, D. M.

Functional effects of nonsynonymous polymorphisms in the human TRPV1 gene

¹Division of Nephrology and Hypertension, Oregon Health and Science University, and ²Portland Veterans Affairs Medical Center, Portland, Oregon

Submitted 25 July 2007 ; accepted in final form 2 October 2007

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 EC₅₀ 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 EC₅₀ 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.

capsaicin; single-nucleotide polymorphism; diabetes