Pirt, a phosphoinositide-binding protein, functions as a regulatory subunit of TRPV1

Cell. 2008 May 2;133(3):475-85. doi: 10.1016/j.cell.2008.02.053.

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is a molecular sensor of noxious heat and capsaicin. Its channel activity can be modulated by several mechanisms. Here we identify a membrane protein, Pirt, as a regulator of TRPV1. Pirt is expressed in most nociceptive neurons in the dorsal root ganglia (DRG) including TRPV1-positive cells. Pirt null mice show impaired responsiveness to noxious heat and capsaicin. Noxious heat- and capsaicin-sensitive currents in Pirt-deficient DRG neurons are significantly attenuated. Heterologous expression of Pirt strongly enhances TRPV1-mediated currents. Furthermore, the C terminus of Pirt binds to TRPV1 and several phosphoinositides, including phosphatidylinositol-4,5-bisphosphate (PIP2), and can potentiate TRPV1. The PIP2 binding is dependent on the cluster of basic residues in the Pirt C terminus and is crucial for Pirt regulation of TRPV1. Importantly, the enhancement of TRPV1 by PIP2 requires Pirt. Therefore, Pirt is a key component of the TRPV1 complex and positively regulates TRPV1 activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Capsaicin / metabolism
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Ganglia, Spinal / metabolism
  • Hot Temperature
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Neurons, Afferent / metabolism
  • Nociceptors / metabolism*
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Sequence Alignment
  • TRPV Cation Channels / metabolism*

Substances

  • Carrier Proteins
  • Membrane Proteins
  • Phosphatidylinositol 4,5-Diphosphate
  • Pirt protein, mouse
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Capsaicin

Associated data

  • GENBANK/EU447173