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      Evolution of acid nociception: ion channels and receptors for detecting acid

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          Abstract

          Nociceptors, i.e. sensory neurons tuned to detect noxious stimuli, are found in numerous phyla of the Animalia kingdom and are often polymodal, responding to a variety of stimuli, e.g. heat, cold, pressure and chemicals, such as acid. Owing to the ability of protons to have a profound effect on ionic homeostasis and damage macromolecular structures, it is no wonder that the ability to detect acid is conserved across many species. To detect changes in pH, nociceptors are equipped with an assortment of different acid sensors, some of which can detect mild changes in pH, such as the acid-sensing ion channels, proton-sensing G protein-coupled receptors and several two-pore potassium channels, whereas others, such as the transient receptor potential vanilloid 1 ion channel, require larger shifts in pH. This review will discuss the evolution of acid sensation and the different mechanisms by which nociceptors can detect acid.

          This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.

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          Most cited references212

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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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            Proton-sensing G-protein-coupled receptors.

            Blood pH is maintained in a narrow range around pH 7.4 mainly through regulation of respiration and renal acid extrusion. The molecular mechanisms involved in pH homeostasis are not completely understood. Here we show that ovarian cancer G-protein-coupled receptor 1 (OGR1), previously described as a receptor for sphingosylphosphorylcholine, acts as a proton-sensing receptor stimulating inositol phosphate formation. The receptor is inactive at pH 7.8, and fully activated at pH 6.8-site-directed mutagenesis shows that histidines at the extracellular surface are involved in pH sensing. We find that GPR4, a close relative of OGR1, also responds to pH changes, but elicits cyclic AMP formation. It is known that the skeleton participates in pH homeostasis as a buffering organ, and that osteoblasts respond to pH changes in the physiological range, but the pH-sensing mechanism operating in these cells was hitherto not known. We detect expression of OGR1 in osteosarcoma cells and primary human osteoblast precursors, and show that these cells exhibit strong pH-dependent inositol phosphate formation. Immunohistochemistry on rat tissue sections confirms the presence of OGR1 in osteoblasts and osteocytes. We propose that OGR1 and GPR4 are proton-sensing receptors involved in pH homeostasis.
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              Impaired pressure sensation in mice lacking TRPV4.

              The sensation of pressure, mechanosensation, in vertebrates remains poorly understood on the molecular level. The ion channel TRPV4 is in the TRP family and is a candidate for a mechanosensitive calcium-permeable channel. It is located in dorsal root ganglia. In the present study, we show that disrupting the Trpv4 gene in mice markedly reduced the sensitivity of the tail to pressure and acidic nociception. The threshold to noxious stimuli and the conduction velocity of myelinated nerve responding to stimuli were also impaired. Activation of unmyelinated nerve was undetected. However, the mouse still retained olfaction, taste sensation, and heat avoidance. The TRPV4 channel expressed in vitro in Chinese hamster ovary cells was opened by low pH, citrate, and inflation but not by heat or capsaicin. These data identify the TRPV4 channel as essential for the normal detection of pressure and as a receptor of the high-threshold mechanosensory complex.
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                Author and article information

                Journal
                Philos Trans R Soc Lond B Biol Sci
                Philos. Trans. R. Soc. Lond., B, Biol. Sci
                RSTB
                royptb
                Philosophical Transactions of the Royal Society B: Biological Sciences
                The Royal Society
                0962-8436
                1471-2970
                11 November 2019
                23 September 2019
                23 September 2019
                : 374
                : 1785 , Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’ organized and edited by Edgar T. Walters and Amanda C. de C. Williams
                : 20190291
                Affiliations
                Department of Pharmacology, University of Cambridge , Tennis Court Road, Cambridge CB2 1PD, UK
                Author notes

                One contribution of 19 to a Theo Murphy meeting issue ‘ Evolution of mechanisms and behaviour important for pain’.

                Author information
                http://orcid.org/0000-0002-2699-1979
                Article
                rstb20190291
                10.1098/rstb.2019.0291
                6790391
                31544616
                55e680bf-eac7-47d1-b058-fd53d13e68da
                © 2019 The Authors.

                Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

                History
                : 27 May 2019
                Funding
                Funded by: Biotechnology and Biological Sciences Research Council, http://dx.doi.org/10.13039/501100000268;
                Award ID: BB/M011194/1
                Funded by: Arthritis Research UK, http://dx.doi.org/10.13039/501100000341;
                Award ID: RG21973
                Categories
                1001
                133
                202
                Articles
                Review Article
                Custom metadata
                November 11, 2019

                Philosophy of science
                acid,acid-sensing ion channel,trp channel,two-pore potassium channel,proton-sensing gpcr,nociception

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