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TRPV3 in Drug Development pharmaceuticals Review TRPV3 in Drug Development Lisa M. Broad 1,*, Adrian J. Mogg 1, Elizabeth Eberle 2, Marcia Tolley 2, Dominic L. Li 3 and Kelly L. Knopp 3 1 Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK; [email protected] 2 Covance Greenfield Laboratories, Greenfield, Indianapolis, IN 46140, USA; [email protected] (E.E.); [email protected] (M.T.) 3 Lilly Research Laboratories, Eli Lilly and Company Inc., Indianapolis, IN 46285, USA; [email protected] (D.L.L.); [email protected] (K.L.K.) * Correspondance: [email protected]; Tel.: +44-1276-483-016 Academic Editors: Arpad Szallasi and Susan M. Huang Received: 1 July 2016; Accepted: 31 August 2016; Published: 9 September 2016 Abstract: Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP (Transient Receptor Potential) super-family. It is a relatively underexplored member of the thermo-TRP sub-family (Figure1), however, genetic mutations and use of gene knock-outs and selective pharmacological tools are helping to provide insights into its role and therapeutic potential. TRPV3 is highly expressed in skin, where it is implicated in skin physiology and pathophysiology, thermo-sensing and nociception. Gain of function TRPV3 mutations in rodent and man have enabled the role of TRPV3 in skin health and disease to be particularly well defined. Pre-clinical studies provide some rationale to support development of TRPV3 antagonists for therapeutic application for the treatment of inflammatory skin conditions, itch and pain. However, to date, only one compound directed towards block of the TRPV3 receptor (GRC15300) has progressed into clinical trials. Currently, there are no known clinical trials in progress employing a TRPV3 antagonist. Keywords: TRPV3; keratinocytes; itch; pain; Olmsted syndrome 1. Introduction TRPV3 is a non-selective cation channel, displaying relatively high permeability to calcium. It was first cloned in 2002 and displays ~30%–40% sequence homology with other TRPV channels. Other features in common include the predicted protein structure encompassing six transmembrane spanning domains (1–6), a pore-forming loop between domains 5–6, cytoplasmic amino and carboxyl termini, ankyrin repeats and coiled-coil domains at the amino terminus and several putative phosphorylation sites [1–3] (see Figure2). The channel is formed from four subunits, with homo-tetrameric TRPV3 receptors being commonly studied. Hetero-tetrameric channels containing TRPV3 and TRPV1, for example, are reported to be able to form by some [3–5], but not all researchers [6]; however, the nature, role and expression of native TRPV3 containing heteromers is far from clear. Pharmaceuticals 2016, 9, 55; doi:10.3390/ph9030055 www.mdpi.com/journal/pharmaceuticals PharmaceuticalsPharmaceuticals 20162016,, 99,, 55 55 22 of of 17 17 Pharmaceuticals 2016, 9, 55 2 of 17 Number of Publications Number of Publications 0 1 4 7 0 1 4 0 0 0 0 08 1 1 1 15 0 0 0 0 0 0 0 0 2 2 2002 2003 2 2005 2006 2 2 2009 20 2 2012 2013 2 2 2016 0 1 4 7 0 1 4 1988-1999 0 0 0 0 08 1 1 1 15 0 0 0 0 0 0 0 0 2 2 2002 2003 2 2005 2006 2 2 2009 20 2 2012 2013 2 2 2016 1988-1999 Figure 1. Figure 1. TotalTotal publications publications per per year year around around TRPV3 TRPV3 (orange (orange bars) bars) relative relative to to other thermo-TRPs (TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1). Data as of 25/05/2016. Searches were conducted using (TRPV1,Figure TRPV2, 1. Total TRPV4, publications TRPM8 per and year TRPA1). around Data TRPV3 as of(orange 25/05/2016. bars) relativeSearches to wereother conductedthermo-TRPs using PubMed and, where applicable, included alternative nomenclature (e.g., TRPV1 and VR1). PubMed(TRPV1, and, TRPV2,where applicable,TRPV4, TRPM8 included and TRPA1). alternative Data asnomenclature of 25/05/2016. (e.g., Searches TRPV1 were and conducted VR1). using PubMed and, where applicable, included alternative nomenclature (e.g., TRPV1 and VR1). Figure 2. Membrane topology of TRPV3. Residues involved in heat activation (N643, I644, N647, Figure 2. Membrane topology of TRPV3. Residues involved in heat activation (N643, I644, N647, L658 and Y661), activation by 2-APB (H426 and R696), Camphor (C612 and C619) and modulation by L658 and Y661), activation by 2-APB (H426 and R696), Camphor (C612 and C619) and modulation by Figurephosphatidylinositol 2. Membrane 4,5-bisphosphatetopology of TRPV3. (PI(4,5)P Residues; R696 invo andlved K705), in heat ATP activati (K169 andon (N643, K174), MgI644,2+ (D641)N647, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2 2; R696 and K705), ATP (K169 and K174), Mg2+ (D641) 2+ L658and Caandand Y661),Ca(R696)2+ (R696) activation are are highlighted, highlighted, by 2-APB in in addition (H426 addition and toto theRthe696), location Camphor of of ankyrin ankyrin (C612 repeats repeatsand C619) [7–13]. [7– 13and ]. modulation by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2; R696 and K705), ATP (K169 and K174), Mg2+ (D641) andIn common CaIn2+ (R696)common with are with otherhighlighted, other TRP channels,TRP in addition channels, TRPV3 to theTRPV3 actslocation asacts a of polymodalas ankyrin a polymodal repeats signal [7–13].signal integrator. integrator. It is activatedIt is by numerousactivated physical by numerous and chemical physical modulatorsand chemical and modulators by posttranslational and by posttranslational modifications, modifications, and the impact of individualInand common the impact stimuli with of is individual influencedother TRP stimuli by channels, the is presence influenced TRPV3 of otherby actsthe stimuli presence as a (seepolymodal of Figureother stimuli3 forsignal summary). (see integrator. Figure TRPV33 for It is summary). TRPV3 is activated by innocuous temperature, with the threshold for channel opening at activatedactivated by innocuousnumerous temperature,physical and withchemical the threshold modulators for channeland by openingposttranslational at 31–39 ◦modifications,C, and activity and the31–39 impact °C, and of individualactivity is retained stimuli over is influenced temperatur esby extending the presence into the of noxiousother stimuli range [14]. (see Chemical Figure 3 for is retainedagonists over include temperatures spice extracts extending (such into as thecamp noxioushor and range carvacrol), [14]. Chemical synthetic agonistsagents (including include spice summary).extracts (such TRPV3 as camphor is activated and carvacrol),by innocuous synthetic temperature, agents (includingwith the threshold 2-aminoethoxy for channel diphenylborate, opening at 31–392-APB) °C, and and endogenous activity is retained ligand farnesyl over temperatur pyrophosphatees extending (FPP), [into1–3, 15the,16 noxious]. Repeated range exposure [14]. Chemical to heat agonists include spice extracts (such as camphor and carvacrol), synthetic agents (including Pharmaceuticals 2016, 9, 55 3 of 17 Pharmaceuticals 2016, 9, 55 3 of 17 2-aminoethoxy diphenylborate, 2-APB) and endogenous ligand farnesyl pyrophosphate (FPP), [1– 3,15,16]. Repeated exposure to heat or chemical agonists leads to sensitization of the receptor [8,17], or chemical agonists leads to sensitization of the receptor [8,17], through hysteresis of gating [14], through hysteresis of gating [14], while co-application of diverse stimuli, such as heat and chemical while co-application of diverse stimuli, such as heat and chemical agonists, is synergistic [17,18]. agonists, is synergistic [17,18]. Activation of Gq coupled GPCRs also sensitizes TRPV3 [19], with key Activation of Gq coupled GPCRs also sensitizes TRPV3 [19], with key components in the downstream components in the downstream signalling cascade including protein kinase C [20], Ca2+-calmodulin signalling cascade including protein kinase C [20], Ca2+-calmodulin [8,10], phosphatidylinositol [8,10], phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) [11] and unsaturated fatty acids [18,20]. 4,5-bisphosphate (PI(4,5)P2)[11] and unsaturated fatty acids [18,20]. Other modulators include Other modulators include voltage [11], ATP [10], Mg2+ [12], and intracellular acidification [21,22]. voltage [11], ATP [10], Mg2+ [12], and intracellular acidification [21,22]. Figure 3. Activators,Activators, inhibitors inhibitors and and modulators modulators of TRPV3. of TRPV3. Quat Quaternaryernary structure structure of TRPV3 of TRPV3 with with compounds and signalling pathways known to activate, inhibit or modulate the receptor. compounds and signalling pathways known to activate, inhibit or modulate the receptor. See See Introduction for references–additional references [23–26]. Introduction for references–additional references [23–26]. The amino amino acid acid residues residues and and regions regions underlying underlying activation activation of TRPV3 of TRPV3 by a number by a number of stimuli of stimulihave been have mapped. been mapped. Information Information relating to relating the mechanism to the mechanism of activation of activation by heat [14,27,28], by heat [2-APB14,27,28 [9]], 2-APBand camphor [9] and camphor[13] is available. [13] is available. Likewise, Likewise, residues residues involved involved in mediating in mediating modulation modulation by byCa2+ Ca/Ca2+2+/Ca-calmodulin;2+-calmodulin; [8,10]; [8 Mg,10];2+ Mg[12];2+ pH[12 ];[21] pH and [21] voltage and voltage [11] have [11]have been been defined defined (Figure (Figure 2. See2, seeYang Yang and and Zhu Zhu for forrecent recent detailed detailed review review [29]. [29 ]). Pharmaceuticals 2016, 9, 55 4 of 17 2. Expression and Function of TRPV3 In contrast to TRPV1, TRPA1 and TRPM8, a direct role for TRPV3 in the peripheral nervous system is controversial, as expression in sensory neurons is not conserved across species, with minimal detection in rodents [1–3,30]. TRPV3 is however expressed in skin keratinocytes (Figure4) across species [1,2,31] and in humans, TRPV3 gene expression in skin is the highest of the >50 tissues profiled in the GTEx project [32] (Supplementary Figure S1). TRPV3 expression is also reported in other epithelial cells including oral and nasal epithelium [19,33], distal colon [34] and cornea [35].
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