Coexpression and activation of TRPV1 suppress the activity of the KCNQ2/3 channel

J Gen Physiol. 2011 Sep;138(3):341-52. doi: 10.1085/jgp.201110618. Epub 2011 Aug 15.

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel expressed predominantly in peripheral nociceptors. By detecting and integrating diverse noxious thermal and chemical stimuli, and as a result of its sensitization by inflammatory mediators, the TRPV1 receptor plays a key role in inflammation-induced pain. Activation of TRPV1 leads to a cascade of pro-nociceptive mechanisms, many of which still remain to be identified. Here, we report a novel effect of TRPV1 on the activity of the potassium channel KCNQ2/3, a negative regulator of neuronal excitability. Using ion influx assays, we revealed that TRPV1 activation can abolish KCNQ2/3 activity, but not vice versa, in human embryonic kidney (HEK)293 cells. Electrophysiological studies showed that coexpression of TRPV1 caused a 7.5-mV depolarizing shift in the voltage dependence of KCNQ2/3 activation compared with control expressing KCNQ2/3 alone. Furthermore, activation of TRPV1 by capsaicin led to a 54% reduction of KCNQ2/3-mediated current amplitude and attenuation of KCNQ2/3 activation. The inhibitory effect of TRPV1 appears to depend on Ca(2+) influx through the activated channel followed by Ca(2+)-sensitive depletion of phosphatidylinositol 4,5-bisphosphate and activation of protein phosphatase calcineurin. We also identified physical interactions between TRPV1 and KCNQ2/3 coexpressed in HEK293 cells and in rat dorsal root ganglia neurons. Mutation studies established that this interaction is mediated predominantly by the membrane-spanning regions of the respective proteins and correlates with the shift of KCNQ2/3 activation. Collectively, these data reveal that TRPV1 activation may deprive neurons from inhibitory control mediated by KCNQ2/3. Such neurons may thus have a lower threshold for activation, which may indirectly facilitate TRPV1 in integrating multiple noxious signals and/or in the establishment or maintenance of chronic pain.

MeSH terms

  • Animals
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • KCNQ2 Potassium Channel / antagonists & inhibitors*
  • KCNQ2 Potassium Channel / metabolism
  • KCNQ3 Potassium Channel / antagonists & inhibitors*
  • KCNQ3 Potassium Channel / metabolism
  • Male
  • Neurons / metabolism
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • TRPV Cation Channels / metabolism*
  • Transfection

Substances

  • KCNQ2 Potassium Channel
  • KCNQ2 protein, human
  • KCNQ3 Potassium Channel
  • Phosphatidylinositol 4,5-Diphosphate
  • TRPV Cation Channels
  • TRPV1 protein, human