Characterization of temperature-sensing and PIP2-regulation of TRPV1 ion channel at the C-terminal domain using NMR spectroscopy and molecular dynamics simulations

Kelly A. Raymond, Edward C. Twomey, Yufeng Wei

Research output: Contribution to journalArticlepeer-review

Abstract

Transient receptor potential (TRP) channels are receptors of stimulating signals, such as temperature, taste, odor, and chemo- and mechanostimuli. Temperature sensing TRP channels coincidently function as pain receptors, and are potential targets for substances of abuse, including alcohol and illicit drugs. TRP vanilloid type 1 (TRPV1) channel is activated by heat (>43 °C) and capsaicin under the tight regulation of membrane- associated second messenger, PIP2 (phosphatidylinositol-4,5-bisphosphate), responds to noxious stimuli and inflammatory substances, and could potentially modulate effects of alcohol and drugs of abuse. Despite the crucial roles in mediating signal transductions at both peripheral and central nervous systems, TRP channels are poorly understood in the context of structures and mechanisms. In this study, we describe our initial structural characterization of the TRPV1 C-terminal domain, the putative temperature sensing and PIP2-regulatory domain, using NMR spectroscopy and molecular dynamics simulations. Both experimental and computational models suggest that the C-terminal domain is intrinsically unstructured at room temperature with and without lipid bicelles. Elevated temperature and PIP2-binding can induce substantial conformational changes and formation of considerable secondary structural components in the C-terminal domain, which could be transduced to the transmembrane domain to potentially sensitize the channel.

Original languageEnglish (US)
Pages (from-to)79-86
Number of pages8
JournalJournal of Integrated OMICS
Volume4
Issue number2
DOIs
StatePublished - Dec 2014
Externally publishedYes

Keywords

  • Membrane protein
  • Molecular dynamics
  • NMR
  • Phospholipids
  • Signal transduction
  • Transient receptor potential channel

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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