title: Activation of TRESK channels by the inflammatory mediator lysophosphatidic acid balances nociceptive signalling.
abstract: In dorsal root ganglia (DRG) neurons TRESK channels constitute a major current component of the standing outward current IKSO. A prominent physiological role of TRESK has been attributed to pain sensation. During inflammation mediators of pain e.g. lysophosphatidic acid (LPA) are released and modulate nociception. We demonstrate co-expression of TRESK and LPA receptors in DRG neurons. Heterologous expression of TRESK and LPA receptors in Xenopus oocytes revealed augmentation of basal K(+) currents upon LPA application. In DRG neurons nociception can result from TRPV1 activation by capsaicin or LPA. Upon co-expression in Xenopus oocytes LPA simultaneously increased both depolarising TRPV1 and hyperpolarising TRESK currents. Patch-clamp recordings in cultured DRG neurons from TRESK[wt] mice displayed increased IKSO after application of LPA whereas under these conditions IKSO in neurons from TRESK[ko] mice remained unaltered. Under current-clamp conditions LPA application differentially modulated excitability in these genotypes upon depolarising pulses. Spike frequency was attenuated in TRESK[wt] neurons and, in contrast, augmented in TRESK[ko] neurons. Accordingly, excitation of nociceptive neurons by LPA is balanced by co-activation of TRESK channels. Hence excitation of sensory neurons is strongly controlled by the activity of TRESK channels, which therefore are good candidates for the treatment of pain disorders.
authors.affiliation: Institute of Physiology, AG Molecular Electrophysiology, University of Würzburg, 97070 Würzburg Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Kollert
authors.affiliation: Institute for Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dombert
authors.affiliation: Institute of Physiology, AG Molecular Electrophysiology, University of Würzburg, 97070 Würzburg Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Döring
authors.affiliation: Institute of Physiology, AG Molecular Electrophysiology, University of Würzburg, 97070 Würzburg Germany.
authors.forename: Erhard
authors.initials: E
authors.lastname: Wischmeyer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014981:Xenopus / Q000254:growth & development
chemical_list: D018836:Inflammation Mediators; D008246:Lysophospholipids; D015221:Potassium Channels; D049368:Receptors, Lysophosphatidic Acid; C486498:Kcnk18 protein, mouse; C032881:lysophosphatidic acid