Direct evidence for functional TRPV1/TRPA1 heteromers

Pflugers Arch. 2014 Dec;466(12):2229-41. doi: 10.1007/s00424-014-1497-z. Epub 2014 Mar 19.

Abstract

Transient receptor potential cation channel, subfamily V, member 1 (TRPV1) plays a key role in sensing environmental hazards and in enhanced pain sensation following inflammation. A considerable proportion of TRPV1-expressing cells also express transient receptor potential cation channel, subfamily A, member 1 (TRPA1). There is evidence for a TRPV1-TRPA1 interaction that is predominantly calcium-dependent, and it has been suggested that the two proteins might form a heteromeric channel. Here, we constructed subunit concatemers to search for direct evidence for such an interaction. We found that a TRPV1::TRPV1 concatemer and TRPV1 formed channels with similar properties. A TRPV1::TRPA1 concatemer was responsive to TRPV1 agonists capsaicin, acidic pH and ethanol, but not to TRPA1 agonists. Isolated TRPV1 and TRPV1::TRPA1 imaged by atomic force microscopy (AFM) both had molecular volumes consistent with the formation of tetrameric channels. Antibodies decorated epitope tags on TRPV1 with a four-fold symmetry, as expected for a homotetramer. In contrast, pairs of antibodies decorated tags on TRPV1::TRPA1 predominantly at 180°, indicating the formation of a channel consisting of two TRPV1::TRPA1 concatemers arranged face to face. TRPV1::TRPA1 was sensitized by PKC activation and could be inhibited by a TRPV1 antagonist. TRPV1::TRPA1 was activated by heat and displayed a threshold and temperature coefficient similar to TRPV1. However, the channel formed by TRPV1::TRPA1 has only two binding sites for capsaicin and shows less total current and a smaller capsaicin-induced shift in voltage-dependent gating than TRPV1::TRPV1 or TRPV1. We conclude that the presence of TRPA1 exerts a functional inhibition on TRPV1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Calcium Channels / chemistry
  • Calcium Channels / metabolism*
  • Capsaicin / pharmacology
  • HEK293 Cells
  • Humans
  • Ion Channel Gating
  • Nerve Tissue Proteins / agonists
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • Protein Binding
  • Protein Multimerization*
  • TRPA1 Cation Channel
  • TRPV Cation Channels / agonists
  • TRPV Cation Channels / chemistry
  • TRPV Cation Channels / metabolism*
  • Transient Receptor Potential Channels / agonists
  • Transient Receptor Potential Channels / chemistry
  • Transient Receptor Potential Channels / metabolism*

Substances

  • Calcium Channels
  • Nerve Tissue Proteins
  • TRPA1 Cation Channel
  • TRPA1 protein, human
  • TRPV Cation Channels
  • TRPV1 protein, human
  • Transient Receptor Potential Channels
  • Capsaicin