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      GI‐530159, a novel, selective, mechanosensitive two‐pore‐domain potassium (K 2P) channel opener, reduces rat dorsal root ganglion neuron excitability

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          Background and Purpose

          TREK two‐pore‐domain potassium (K 2P) channels play a critical role in regulating the excitability of somatosensory nociceptive neurons and are important mediators of pain perception. An understanding of the roles of TREK channels in pain perception and, indeed, in other pathophysiological conditions, has been severely hampered by the lack of potent and/or selective activators and inhibitors. In this study, we describe a new, selective opener of TREK channels, GI‐530159.

          Experimental Approach

          The effect of GI‐530159 on TREK channels was demonstrated using 86Rb efflux assays, whole‐cell and single‐channel patch‐clamp recordings from recombinant TREK channels. The expression of K 2P2.1 (TREK1), K 2P10.1 (TREK2) and K 2P4.1 (TRAAK) channels was determined using transcriptome analysis from single dorsal root ganglion (DRG) cells. Current‐clamp recordings from cultured rat DRG neurons were used to measure the effect of GI‐530159 on neuronal excitability.

          Key Results

          For recombinant human TREK1 channels, GI‐530159 had similar low EC 50 values in Rb efflux experiments and electrophysiological recordings. It activated TREK2 channels, but it had no detectable action on TRAAK channels nor any significant effect on other K channels tested. Current‐clamp recordings from cultured rat DRG neurones showed that application of GI‐530159 at 1 μM resulted in a significant reduction in firing frequency and a small hyperpolarization of resting membrane potential.

          Conclusions and Implications

          This study provides pharmacological evidence for the presence of mechanosensitive TREK K 2P channels in sensory neurones and suggests that development of selective K 2P channel openers like GI‐530159 could aid in the development of novel analgesic agents.

          Linked Articles

          This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit

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          Most cited references 44

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          Molecular background of leak K+ currents: two-pore domain potassium channels.

          Two-pore domain K(+) (K(2P)) channels give rise to leak (also called background) K(+) currents. The well-known role of background K(+) currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K(2P) channel types) that this primary hyperpolarizing action is not performed passively. The K(2P) channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K(2P) channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K(2P) channel family into the spotlight. In this review, we focus on the physiological roles of K(2P) channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.
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            Nociceptors--noxious stimulus detectors.

            In order to deal effectively with danger, it is imperative to know about it. This is what nociceptors do--these primary sensory neurons are specialized to detect intense stimuli and represent, therefore, the first line of defense against any potentially threatening or damaging environmental inputs. By sensing noxious stimuli and contributing to the necessary reactions to avoid them--rapid withdrawal and the experience of an intensely unpleasant or painful sensation, nociceptors are essential for the maintenance of the body's integrity. Although nociceptive pain is clearly an adaptive alarm system, persistent pain is maladaptive, essentially an ongoing false alarm. Here, we highlight the genesis of nociceptors during development and the intrinsic properties of nociceptors that enable them to transduce, conduct, and transmit nociceptive information and also discuss how their phenotypic plasticity contributes to clinical pain.
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              Regulating excitability of peripheral afferents: emerging ion channel targets.

              The transmission and processing of pain signals relies critically on the activities of ion channels that are expressed in afferent pain fibers. This includes voltage-gated channels, as well as background (or leak) channels that collectively regulate resting membrane potential and action potential firing properties. Dysregulated ion channel expression in response to nerve injury and inflammation results in enhanced neuronal excitability that underlies chronic neuropathic and inflammatory pain. Pharmacological modulators of ion channels, particularly those that target channels on peripheral neurons, are being pursued as possible analgesics. Over the past few years, a number of different types of ion channels have been implicated in afferent pain signaling. Here we give an overview of recent advances on sodium, calcium, potassium and chloride channels that are emerging as especially attractive targets for the treatment of pain.

                Author and article information

                Br J Pharmacol
                Br. J. Pharmacol
                British Journal of Pharmacology
                John Wiley and Sons Inc. (Hoboken )
                29 December 2017
                June 2018
                29 December 2017
                : 175
                : 12 , Themed Section: Recent Advances in Targeting Ion Channels to Treat Chronic Pain. Guest Editors: Edward B Stevens and Gary J Stephens ( doiID: 10.1111/bph.v175.12 )
                : 2272-2283
                [ 1 ] Pfizer NPRU Cambridge UK
                [ 2 ] Icagen Durham NC USA
                [ 3 ] Medway School of Pharmacy University of Kent Chatham Maritime Kent UK
                Author notes
                [* ] Correspondence Alistair Mathie, Medway School of Pharmacy, University of Kent, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK. E‐mail: a.a.mathie@

                Joint corresponding authors.

                BPH14098 2017-BJP-1385-RPT-G
                © 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

                This is an open access article under the terms of the License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 7, Tables: 0, Pages: 12, Words: 6949
                Funded by: Biotechnology and Biological Sciences Research Council (UK)
                Award ID: BB/J000930/1
                Research Paper
                Themed Section: Research Papers
                Custom metadata
                June 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.0 mode:remove_FC converted:31.05.2018

                Pharmacology & Pharmaceutical medicine


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