title: Coexpression and activation of TRPV1 suppress the activity of the KCNQ2/3 channel.
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.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Zhang
authors.forename: Ping
authors.initials: P
authors.lastname: Han
authors.forename: Torben R
authors.initials: TR
authors.lastname: Neelands
authors.forename: Steve
authors.initials: S
authors.lastname: McGaraughty
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Carol S
authors.initials: CS
authors.lastname: Surowy
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051659:KCNQ3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000378:metabolism*; D014162:Transfection
chemical_list: D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; D019269:Phosphatidylinositol 4,5-Diphosphate; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human