Functional effects of nonsynonymous polymorphisms in the human TRPV1 gene

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

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

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 TRPV1I315M and TRPV1P91S variants (relative to TRPV1WT), 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 (TRPV1P91S) or only very modestly increased (TRPV1I315M). 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). In aggregate, these data underscore expression-level and functional differences among naturally occurring TRPV1 variants; the implications with respect to human physiology are considered.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume293
Issue number6
DOIs
StatePublished - Dec 2007

Fingerprint

Capsaicin
Genes
Neurogenic Inflammation
Transient Receptor Potential Channels
Nociception
HEK293 Cells
Haplotypes
Single Nucleotide Polymorphism
Messenger RNA
Mutation
Population

Keywords

  • Capsaicin
  • Diabetes
  • Single-nucleotide polymorphism

ASJC Scopus subject areas

  • Physiology

Cite this

Functional effects of nonsynonymous polymorphisms in the human TRPV1 gene. / Xu, Hongshi; Tian, Wei; Fu, Yi; Oyama, Terry T.; Anderson, Sharon; Cohen, David.

In: American Journal of Physiology - Renal Physiology, Vol. 293, No. 6, 12.2007.

Research output: Contribution to journalArticle

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