DOCSLIB.ORG

(TRP) Channels

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(TRP) Channels A thermodynamic framework for understanding temperature sensing by transient receptor potential (TRP) channels David E. Claphama,1 and Christopher Millerb,1 aDepartment of Cardiology, Howard Hughes Medical Institute, Manton Center for Orphan Disease, Children’s Hospital Boston, and Department of Neurobiology, Harvard Medical School, Boston, MA 02115; and bDepartment of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02454 This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2006. Contributed by David E. Clapham, October 24, 2011 (sent for review October 15, 2011) The exceptionally high temperature sensitivity of certain transient responses arise from the same type of conformational change upon receptor potential (TRP) family ion channels is the molecular basis of channel opening. Hence, the search for domain differences between hot and cold sensation in sensory neurons. The laws of thermody- hot- and cold-sensing TRPs is an exercise in futility. (ii)Allhot- namics dictate that opening of these specialized TRP channels must sensing TRPs are also cold-sensing TRPs, and vice versa. (iii)The involve an unusually large conformational standard-state enthalpy, source of high temperature sensitivity is a difference in heat capacity ΔHo:positiveΔHo for heat-activated and negative ΔHo for cold-ac- between the channel’s open vs. its closed conformation. tivated TRPs. However, the molecular source of such high-enthalpy changes has eluded neurobiologists and biophysicists. Here we offer Results a general, unifying mechanism for both hot and cold activation that Basic Thermodynamic Considerations. We consider a protein in recalls long-appreciated principles of protein folding. We suggest equilibrium between two conformations, A and B. that TRP channel gating is accompanied by large changes in molar heat capacity, ΔCP. This postulate, along with the laws of thermo- A ⇔ B [1] dynamics and independent of mechanistic detail, leads to the con- clusion that hot- and cold-sensing TRPs operate by identical con- with equilibrium constant K: formational changes. ¼½ =½ ¼ =ð − Þ [2A] K B A pB 1 pB TRPV | TRPM8 | TRPC5 | hydrophobic interaction ¼ =ð þ Þ [2B] pB K 1 K any membrane proteins are signal integrators evolved to “ ” respond to extracellular ligands, intracellular signal trans- where the bracket form represents concentrations of A or B at M “ ” duction, and transmembrane voltage changes. Our sensory nerves equilibrium, and the probability form represents, equivalently, use specialized ion-channel proteins to report environmental the probability of the appearance of B. We assume that K may temperatures, most notably, but not exclusively, the transient re- be determined experimentally. Stationary-state single-channel re- ceptor potential (TRP) ion channels (1–3). The TRPV1 channels cording, for instance, would provide a direct measure of pB,ifB ’ in sensory nerves respond to heat and also to capsaicin, an alkaloid would represent the channel s open state and A the closed, as in a from “hot” peppers, which binds to open the channel and thus thorough analysis of TRPV1 (9). K is of course a function of both depolarizes the neuron and fires action potentials (4). The brain, temperature and pressure; for this discussion, we consider pressure fi interpreting this information as an increase in ambient tempera- xed and will ask how K is expected to vary with temperature, T. ture, initiates vasodilation and sweating. Conversely, drugs that The fundamental relation of chemical thermodynamics, which block TRPV1 input to the brain provoke hypothalamic-mediated follows from the First and Second Laws, relates the measured Δ o changes in metabolism that elevate body temperature (5). The value of K to the change in standard-state Gibbs free energy, G : cold-sensing counterpart of TRPV1 is TRPM8, which binds ΔG8 ¼ − RT lnK; [3] ligands like menthol or icilin to counterfeit cold sensation (6, 7). When injected into animals, icilin induces shivering to raise body where R is the gas constant and ΔGo is the intrinsic difference in temperature (8). Here we discuss how proteins like TRPV1 and Gibbs free energy between the two conformational states at a given TRPM8 are tuned for robust responses to small differences in temperature and pressure. Because at a given temperature, temperature over a narrow range. This study offers a model-free framework for understanding the ΔG8 ¼ ΔH8 − TΔS8 [4A] temperature sensitivities of various TRP channels. We address two types of questions. First, how can the temperature sensitivity of ¼ − Δ 8= þ Δ 8= : [4B] channel opening be so high? Second, what sorts of differences lnK H RT S R fi should we expect to nd between heat-activated TRPs like TRPV1 ΔGo and K in general vary with T. In the simplest case, with ΔHo and cold-activated TRPs like TRPM8, or indeed between these and ΔSo temperature-independent, ΔGo changes linearly with T, and the many TRPs that are relatively insensitive to temperature? By increasing or decreasing depending on the sign of ΔSo, and lnK “model-free,” we mean that the conclusions here emerge directly from the laws of thermodynamics, with a few conventional auxiliary assumptions. The behavior to be described is therefore necessary Author contributions: D.E.C. and C.M. designed research, performed research, and wrote and inescapable—the only question is whether the particular pa- the paper. rameters involved are of such magnitude to be relevant to temper- The authors declare no conflict of interest. ature-sensing TRP channels. The main conclusions of this thermo- 1To whom correspondence may be addressed. E-mail: [email protected] dynamic treatment are as follows. (i) Hot-sensing and cold-sensing or [email protected]. 19492–19497 | PNAS | December 6, 2011 | vol. 108 | no. 49 www.pnas.org/cgi/doi/10.1073/pnas.1117485108 Downloaded by guest on September 27, 2021 varies inversely with T, increasing or decreasing depending on the probability, would vary with T. However, as has been long appre- o sign of ΔH . Although Eqs. 4A and 4B are equivalent, we focus ciated by physical biochemists (23, 24), proteins do not generally INAUGURAL ARTICLE here on the T-dependence of K, because this is so closely related behave this way. It is a fundamental error to assume that ΔHo and to measurables like TRP channel activity. Notice from Eq. 4 that ΔSo are T-independent for processes involving proteins—confor- as T increases, the relative contribution of ΔHo to the value of K mational change, folding, etc. (25)—because proteins can exhibit diminishes and that of ΔSo becomes increasingly dominant. high molar heat capacity. Thermodynamic laws demand that The temperature sensitivity of K follows from Eq. 4B: whenever a conformational change is accompanied by a change in o o molar heat capacity (ΔCP), ΔH and ΔS must both vary with T: dlnK=dð1=TÞ¼ − ΔH8=R [5A] ΔH8ðTÞ¼ΔH8ðT0ÞþΔCPðT − T0Þ¼ΔH80 þ ΔCPðT − T0Þ o Thus, if ΔH is T-independent, as customarily assumed in analysis [7A] of TRP channels, a van’tHoffplot—lnK vs. 1/T—will be linear, with slope yielding ΔHo. An alternative measure of T sensitivity is Δ 8ð Þ¼Δ 8ð ÞþΔ ð = Þ¼Δ 8 þ Δ ð = Þ often used: S T S T0 CP ln T T0 S0 CP ln T T0 [7B] dlnK=dT ¼ ΔH8=RT2: [5B] Here, T0 represents an arbitrarily chosen reference temperature, o Δ o Δ o Δ o Δ o If the reaction is energetically unfavorable (ΔH positive), the and H 0 and S 0 are the particular values of H and S at T0. slope of lnK with respect to T will be positive: K increases with T. Therefore, K will vary with T in a more complicated way than the ’ Δ — This happens because the unfavorable contribution of ΔHo to ΔGo van t Hoff line above. As long as CP itself is independent of T becomes less influential at higher T, as indicated in Eq. 4.An a good approximation for protein behavior under typical physio- — fi empirical measure of T sensitivity, often used in TRP channel logical conditions (26) we can predict with con dence the ex- plicit form of K(T): electrophysiology, is Q10, the ratio of K (or of activation rates, which do not concern us here) at two temperatures 10° apart lnKðTÞ¼ − ΔH8=RT − ΔC ð1 − T =TÞ=R (usually measured at 20 °C and 30 °C, but sometimes over varying 0 P 0 [8] temperature ranges): þ ΔS80=R − ðΔCP=RÞlnðT0=TÞ: Q10 ¼ KðT þ 10Þ=KðTÞ: [6A] We also note that K0, the value of K at the reference temperature, is: o Q10 is related to ΔH : À Á lnK0 ¼ − ΔH80=RT0 þ ΔS80=R: [9] 2 ΔH8 ¼ RT lnQ10 10 ≈ 20lnQ10 [6B] Substituting this into Eq. 8 gives us a practical, working relation at physiological temperatures (kcal/mol). for K(T): o Table 1 reports Q10 and corresponding ΔH values for various — lnKðTÞ¼lnK þðΔH8=T − ΔC Þð1 − T =TÞ=R NEUROSCIENCE TRP channels. These enthalpies 100 kcal/mol is not un- 0 0 0 P 0 [10] — common are unusually large values for protein conformational − ðΔCP=RÞlnðT0=TÞ: changes; they challenge us to understand why these TRPs re- quire such large energies to open or close. It is this challenge that This rather opaque function has a remarkable property: regardless motivates the following analysis. of the parameter values, it is always nonmonotonic. If ΔCP is positive (greater heat capacity in conformation B than in A), the Crucial Role of Heat Capacity. If ΔHo and ΔSo for the conforma- plot must be U-shaped, as in Fig. 1. In other words, K(T) will have tional change were both independent of temperature, we would a minimum value, and the steepness of the K–T curve continually immediately know from Eq.
Load more

Recommended publications
  • Pepperspray, CS, & Other 'Less-Lethal' Weapons
    CONTENTS: Protective Measures: p.26-27 Pepperspray: p.2-9, 14-15 Chemical Data Table: p.30 CS/CN: p.10-16 Risk Groups: p.14-15 When to do what / Other Gas Types: p. 12 Asthma: p.14 treatment algorithm: p.4 Rubber Bullets: p.19-21 Nightsticks/Batons: p.17 LAW: p.6 Concussion Grenades: p.22 CR: p.12 VOFIBA: p.7 Fear: p.24 CA: p.12 Making Remedies: p.13 Tasers: p.18 DM: p.12 Sample Card for Handing Out: Shamelessly adapted from the Black Cross Radical Health Collective, www.blackcrosscollective.org If your condition is worsening, go to an emergency room. Basic preparations: Stick with your buddy. Pepperspray, CS, & Other Work with an affinity group. Bring water. Vulnerable people like asthmatics may want to “Less-Lethal” Weapons (your logo here) avoid chemical weapons. You must remove small children from the area BEFORE Used by Rioting Police to Suppress Dissent chemical weapons are used. Check out our w h e n P o l i t r i c k s & Te l e v i s i o n f a i l t o d o s o . website <www.---.org> for lots more info on how to prepare. v3.3 Useful Numbers: Serious injuries: If you don’t know how to treat Medical Emergency: 911 an injury, get a medic, or call 911. Don’t treat Copwatch: 123-4560 someone if you don’t know how. If you are Convergence Ctr Aid Station:123-4567 injured by the police, get to a nurse practitioner, Aftercare Clinic: 123-4568 physician’s assistant, or doctor immediately Legal Team: 123-4565 and have your injury documented in case you Public Defenders: 123-4569 decide to sue.
    [Show full text]
  • TRPM8 Activation by Menthol, Icilin, and Cold Is Differenially Modulated by Intracellular Ph
    5364 • The Journal of Neuroscience, June 9, 2004 • 24(23):5364–5369 Cellular/Molecular TRPM8 Activation by Menthol, Icilin, and Cold Is Differentially Modulated by Intracellular pH David A. Andersson, Henry W. N. Chase, and Stuart Bevan Novartis Institute for Medical Sciences, London WC1E 6BN, United Kingdom TRPM8 is a nonselective cation channel activated by cold and the cooling compounds menthol and icilin (Peier et al., 2002). Here, we have used electrophysiology and the calcium-sensitive dye Fura-2 to study the effect of pH and interactions between temperature, pH, and the two chemical agonists menthol and icilin on TRPM8 expressed in Chinese hamster ovary cells. Menthol, icilin, and cold all evoked 2ϩ ϩ stimulus-dependent [Ca ]i responses in standard physiological solutions of pH 7.3. Increasing the extracellular [H ] from pH 7.3 to approximately pH 6 abolished responses to icilin and cold stimulation but did not affect responses to menthol. Icilin concentration– response curves were significantly shifted to the right when pH was lowered from 7.3 to 6.9, whereas those with menthol were unaltered in solutions of pH 6.1. When cells were exposed to solutions in the range of pH 8.1–6.5, the temperature threshold for activation was elevatedathigherpHanddepressedatlowerpH.Superfusingcellswithalowsubactivatingconcentrationoficilinormentholelevatedthe 2ϩ threshold for cold activation at pH 7.4, but cooling failed to evoke [Ca ]i responses at pH 6 in the presence of either agonist. In voltage-clamp experiments in which the intracellular pH was buffered to different levels, acidification reduced the current amplitude of icilin responses and shifted the threshold for cold activation to lower values with half-maximal inhibition at pH 7.2 and pH 7.6.
    [Show full text]
  • Regulation of TRP Channels by Steroids
    General and Comparative Endocrinology xxx (2014) xxx–xxx Contents lists available at ScienceDirect General and Comparative Endocrinology journal homepage: www.elsevier.com/locate/ygcen Review Regulation of TRP channels by steroids: Implications in physiology and diseases ⇑ Ashutosh Kumar, Shikha Kumari, Rakesh Kumar Majhi, Nirlipta Swain, Manoj Yadav, Chandan Goswami School of Biology, National Institute of Science Education and Research, Sachivalaya Marg, Bhubaneswar, Orissa 751005, India article info abstract Article history: While effects of different steroids on the gene expression and regulation are well established, it is proven Available online xxxx that steroids can also exert rapid non-genomic actions in several tissues and cells. In most cases, these non-genomic rapid effects of steroids are actually due to intracellular mobilization of Ca2+- and other ions Keywords: suggesting that Ca2+ channels are involved in such effects. Transient Receptor Potential (TRP) ion TRP channels channels or TRPs are the largest group of non-selective and polymodal ion channels which cause Ca2+- Steroids influx in response to different physical and chemical stimuli. While non-genomic actions of different Non-genomic action of steroids steroids on different ion channels have been established to some extent, involvement of TRPs in such Ca2+-influx functions is largely unexplored. In this review, we critically analyze the literature and summarize how Expression different steroids as well as their metabolic precursors and derivatives can exert non-genomic effects by acting on different TRPs qualitatively and/or quantitatively. Such effects have physiological repercus- sion on systems such as in sperm cells, immune cells, bone cells, neuronal cells and many others.
    [Show full text]
  • Snapshot: Mammalian TRP Channels David E
    SnapShot: Mammalian TRP Channels David E. Clapham HHMI, Children’s Hospital, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA TRP Activators Inhibitors Putative Interacting Proteins Proposed Functions Activation potentiated by PLC pathways Gd, La TRPC4, TRPC5, calmodulin, TRPC3, Homodimer is a purported stretch-sensitive ion channel; form C1 TRPP1, IP3Rs, caveolin-1, PMCA heteromeric ion channels with TRPC4 or TRPC5 in neurons -/- Pheromone receptor mechanism? Calmodulin, IP3R3, Enkurin, TRPC6 TRPC2 mice respond abnormally to urine-based olfactory C2 cues; pheromone sensing 2+ Diacylglycerol, [Ca ]I, activation potentiated BTP2, flufenamate, Gd, La TRPC1, calmodulin, PLCβ, PLCγ, IP3R, Potential role in vasoregulation and airway regulation C3 by PLC pathways RyR, SERCA, caveolin-1, αSNAP, NCX1 La (100 µM), calmidazolium, activation [Ca2+] , 2-APB, niflumic acid, TRPC1, TRPC5, calmodulin, PLCβ, TRPC4-/- mice have abnormalities in endothelial-based vessel C4 i potentiated by PLC pathways DIDS, La (mM) NHERF1, IP3R permeability La (100 µM), activation potentiated by PLC 2-APB, flufenamate, La (mM) TRPC1, TRPC4, calmodulin, PLCβ, No phenotype yet reported in TRPC5-/- mice; potentially C5 pathways, nitric oxide NHERF1/2, ZO-1, IP3R regulates growth cones and neurite extension 2+ Diacylglycerol, [Ca ]I, 20-HETE, activation 2-APB, amiloride, Cd, La, Gd Calmodulin, TRPC3, TRPC7, FKBP12 Missense mutation in human focal segmental glomerulo- C6 potentiated by PLC pathways sclerosis (FSGS); abnormal vasoregulation in TRPC6-/-
    [Show full text]
  • Transient Receptor Potential Channels and Metabolism
    Molecules and Cells Minireview Transient Receptor Potential Channels and Metabolism Subash Dhakal and Youngseok Lee* Department of Bio and Fermentation Convergence Technology, Kookmin University, BK21 PLUS Project, Seoul 02707, Korea *Correspondence: [email protected] https://doi.org/10.14348/molcells.2019.0007 www.molcells.org Transient receptor potential (TRP) channels are nonselective Montell, 2007). These cationic channels were first charac- cationic channels, conserved among flies to humans. Most terized in the vinegar fly, Drosophila melanogaster. While TRP channels have well known functions in chemosensation, a visual mechanism using forward genetic screening was thermosensation, and mechanosensation. In addition to being studied, a mutant fly showed a transient response to being sensing environmental changes, many TRP channels constant light instead of the continuous electroretinogram are also internal sensors that help maintain homeostasis. response recorded in the wild type (Cosens and Manning, Recent improvements to analytical methods for genomics 1969). Therefore, the mutant was named as transient recep- and metabolomics allow us to investigate these channels tor potential (trp). In the beginning, researchers had spent in both mutant animals and humans. In this review, we two decades discovering the trp locus with the germ-line discuss three aspects of TRP channels, which are their role transformation of the genomic region (Montell and Rubin, in metabolism, their functional characteristics, and their 1989). Using a detailed structural permeation property anal- role in metabolic syndrome. First, we introduce each TRP ysis in light-induced current, the TRP channel was confirmed channel superfamily and their particular roles in metabolism. as a six transmembrane domain protein, bearing a structural Second, we provide evidence for which metabolites TRP resemblance to a calcium-permeable cation channel (Mon- channels affect, such as lipids or glucose.
    [Show full text]
  • Trpa1) Activity by Cdk5
    MODULATION OF TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY A, MEMBER 1 (TRPA1) ACTIVITY BY CDK5 A dissertation submitted to Kent State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Michael A. Sulak December 2011 Dissertation written by Michael A. Sulak B.S., Cleveland State University, 2002 Ph.D., Kent State University, 2011 Approved by _________________, Chair, Doctoral Dissertation Committee Dr. Derek S. Damron _________________, Member, Doctoral Dissertation Committee Dr. Robert V. Dorman _________________, Member, Doctoral Dissertation Committee Dr. Ernest J. Freeman _________________, Member, Doctoral Dissertation Committee Dr. Ian N. Bratz _________________, Graduate Faculty Representative Dr. Bansidhar Datta Accepted by _________________, Director, School of Biomedical Sciences Dr. Robert V. Dorman _________________, Dean, College of Arts and Sciences Dr. John R. D. Stalvey ii TABLE OF CONTENTS LIST OF FIGURES ............................................................................................... iv LIST OF TABLES ............................................................................................... vi DEDICATION ...................................................................................................... vii ACKNOWLEDGEMENTS .................................................................................. viii CHAPTER 1: Introduction .................................................................................. 1 Hypothesis and Project Rationale
    [Show full text]
  • (TRPM8) by Calcium-Rich Particulate Materials and Effects on Human
    Molecular Pharmacology Fast Forward. Published on October 16, 2017 as DOI: 10.1124/mol.117.109959 This article has not been copyedited and formatted. The final version may differ from this version. MOL #109959 Title: Activation of Human Transient Receptor Potential Melastatin-8 (TRPM8) by Calcium- Rich Particulate Materials and Effects on Human Lung Cells Authors: John G. Lamb, Erin G. Romero, Zhenyu Lu, Seychelle K. Marcus, Hannah C. Peterson, John M. Veranth, Cassandra E. Deering-Rice, and Christopher A. Reilly Affiliations: (J.G.L., E.G.R., Z.L., S.K.M., H.C.P., J.M.V., C.E.D-R., and C.A.R.) Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, 30 S. 2000 E., Room 201 Skaggs Hall, Salt Lake City, UT 84112, USA. Downloaded from molpharm.aspetjournals.org at ASPET Journals on September 27, 2021 1 Molecular Pharmacology Fast Forward. Published on October 16, 2017 as DOI: 10.1124/mol.117.109959 This article has not been copyedited and formatted. The final version may differ from this version. MOL #109959 Running Title: Activation of TRPM8 by Particles *Corresponding author: Dr. Christopher A. Reilly, Ph.D. University of Utah Department of Pharmacology and Toxicology 30 South 2000 East, 201 Skaggs Hall Salt Lake City, UT 84112 Phone: (801) 581-5236; FAX: (801) 585-5111 Email: [email protected] Number of text pages: 41 Downloaded from Number of Tables: 2 Number of Figures: 7 References: 40 Number of words in Abstract: 245 Number of words in Introduction: 704 molpharm.aspetjournals.org Number
    [Show full text]
  • Properties and Therapeutic Potential of Transient Receptor Potential Channels with Putative Roles in Adversity: Focus on TRPC5, TRPM2 and TRPA1
    724 Current Drug Targets, 2011, 12, 724-736 Properties and Therapeutic Potential of Transient Receptor Potential Channels with Putative Roles in Adversity: Focus on TRPC5, TRPM2 and TRPA1 L.H. Jiang, N. Gamper and D.J. Beech* Institute of Membrane and Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK Abstract: Mammals contain 28 genes encoding Transient Receptor Potential (TRP) proteins. The proteins assemble into cationic channels, often with calcium permeability. Important roles in physiology and disease have emerged and so there is interest in whether the channels might be suitable therapeutic drug targets. Here we review selected members of three subfamilies of mammalian TRP channel (TRPC5, TRPM2 and TRPA1) that show relevance to sensing of adversity by cells and biological systems. Summarized are the cellular and tissue distributions, general properties, endogenous modulators, protein partners, cellular and tissue functions, therapeutic potential, and pharmacology. TRPC5 is stimulated by receptor agonists and other factors that include lipids and metal ions; it heteromultimerises with other TRPC proteins and is involved in cell movement and anxiety control. TRPM2 is activated by hydrogen peroxide; it is implicated in stress-related inflammatory, vascular and neurodegenerative conditions. TRPA1 is stimulated by a wide range of irritants including mustard oil and nicotine but also, controversially, noxious cold and mechanical pressure; it is implicated in pain and inflammatory responses, including in the airways. The channels have in common that they show polymodal stimulation, have activities that are enhanced by redox factors, are permeable to calcium, and are facilitated by elevations of intracellular calcium. Developing inhibitors of the channels could lead to new agents for a variety of conditions: for example, suppressing unwanted tissue remodeling, inflammation, pain and anxiety, and addressing problems relating to asthma and stroke.
    [Show full text]
  • Cannabinoid Ligands Targeting TRP Channels By
    Cannabinoid ligands targeting TRP channels By: Chanté Muller, Paula Morales, and Patricia H. Reggio Muller, C., Morales, P., & Reggio, P.H. (2019). Cannabinoid ligands targeting TRP channels. Frontiers in Molecular Neuroscience, 11, 497. https://doi.org/10.3389/fnmol.2018.00487 © 2019 Muller, Morales and Reggio. Published under a Creative Commons Attribution International License (CC BY 4.0); https://creativecommons.org/licenses/by/4.0/. Abstract: Transient receptor potential (TRP) channels are a group of membrane proteins involved in the transduction of a plethora of chemical and physical stimuli. These channels modulate ion entry, mediating a variety of neural signaling processes implicated in the sensation of temperature, pressure, and pH, as well as smell, taste, vision, and pain perception. Many diseases involve TRP channel dysfunction, including neuropathic pain, inflammation, and respiratory disorders. In the pursuit of new treatments for these disorders, it was discovered that cannabinoids can modulate a certain subset of TRP channels. The TRP vanilloid (TRPV), TRP ankyrin (TRPA), and TRP melastatin (TRPM) subfamilies were all found to contain channels that can be modulated by several endogenous, phytogenic, and synthetic cannabinoids. To date, six TRP channels from the three subfamilies mentioned above have been reported to mediate cannabinoid activity: TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8. The increasing data regarding cannabinoid interactions with these receptors has prompted some researchers to consider these TRP channels to be “ionotropic cannabinoid receptors.” Although CB1 and CB2 are considered to be the canonical cannabinoid receptors, there is significant overlap between cannabinoids and ligands of TRP receptors. The first endogenous agonist of TRPV1 to be discovered was the endocannabinoid, anandamide (AEA).
    [Show full text]
  • TRPV1: Structure, Endogenous Agonists, and Mechanisms
    International Journal of Molecular Sciences Review TRPV1: Structure, Endogenous Agonists, and Mechanisms Miguel Benítez-Angeles, Sara Luz Morales-Lázaro, Emmanuel Juárez-González and Tamara Rosenbaum * Departamento de Neurociencia Cognitiva, División Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico; [email protected] (M.B.-A.); [email protected] (S.L.M.-L.); [email protected] (E.J.-G.) * Correspondence: [email protected]; Tel.: +52-555-622-56-24; Fax: +52-555-622-56-07 Received: 1 April 2020; Accepted: 29 April 2020; Published: 12 May 2020 Abstract: The Transient Receptor Potential Vanilloid 1 (TRPV1) channel is a polymodal protein with functions widely linked to the generation of pain. Several agonists of exogenous and endogenous nature have been described for this ion channel. Nonetheless, detailed mechanisms and description of binding sites have been resolved only for a few endogenous agonists. This review focuses on summarizing discoveries made in this particular field of study and highlighting the fact that studying the molecular details of activation of the channel by different agonists can shed light on biophysical traits that had not been previously demonstrated. Keywords: TRP channels; TRPV1; pain; agonist; structure 1. Introduction Since the Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel was cloned in the last years of the 20th century [1], there have been extensive efforts to reveal the structural and functional details of this protein. Thus, nowadays it is one of the best characterized members of the TRP family of ion channels. TRPV1 is mainly expressed by trigeminal ganglion (TG) neurons and by small-diameter neurons within sensory ganglia such as the dorsal root ganglion (DRG).
    [Show full text]
  • Joint Diseases
    EuropeanO Krupkova Cells et al.and Materials Vol. 34 2017 (pages 180-201) DOI: 10.22203/eCM.v034a12 TRP channels in ISSN joint 1473-2262 diseases THE ROLE OF TRANSIENT RECEPTOR POTENTIAL CHANNELS IN JOINT DISEASES O. Krupkova1,*, J. Zvick1 and K. Wuertz-Kozak1,2,3,4 1 Department of Health Sciences and Technology, Institute for Biomechanics, ETH Zurich, Zurich, Switzerland 2 Department of Health Sciences, Institute of Sociology of Health and Physical Activity, University of Potsdam, Potsdam, Germany 3 Schön Clinic Munich Harlaching, Munich, Germany 4 Spine Centre, Academic Teaching Hospital and Spine Research, Paracelsus Medical University, Salzburg, Austria Abstract Transient receptor potential channels (TRP channels) are cation selective transmembrane receptors with diverse structures, activation mechanisms and physiological functions. TRP channels act as cellular sensors for a plethora of stimuli, including temperature, membrane voltage, oxidative stress, mechanical stimuli, pH and endogenous as well as exogenous ligands, thereby illustrating their versatility. As such, TRP channels regulate various functions in both excitable and non-excitable cells, mainly by mediating Ca2+ homeostasis. Dysregulation of TRP channels is implicated in many pathologies, including cardiovascular diseases, muscular dystrophies and hyperalgesia. However, the importance of TRP channel expression, physiological function and regulation in chondrocytes and intervertebral disc (IVD) cells is largely unexplored. Osteoarthritis (OA) and degenerative disc disease (DDD) are chronic age-related disorders that significantly affect the quality of life by causing pain, activity limitation and disability. Furthermore, currently available therapies cannot effectively slow-down or stop progression of these diseases. Both OA and DDD are characterised by reduced tissue cellularity, enhanced inflammatory responses and molecular, structural and mechanical alterations of the extracellular matrix, hence affecting load distribution and reducing joint flexibility.
    [Show full text]
  • TRPM Channels in Human Diseases
    cells Review TRPM Channels in Human Diseases 1,2, 1,2, 1,2 3 4,5 Ivanka Jimenez y, Yolanda Prado y, Felipe Marchant , Carolina Otero , Felipe Eltit , Claudio Cabello-Verrugio 1,6,7 , Oscar Cerda 2,8 and Felipe Simon 1,2,7,* 1 Faculty of Life Science, Universidad Andrés Bello, Santiago 8370186, Chile; [email protected] (I.J.); [email protected] (Y.P.); [email protected] (F.M.); [email protected] (C.C.-V.) 2 Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Universidad de Chile, Santiago 8380453, Chile; [email protected] 3 Faculty of Medicine, School of Chemistry and Pharmacy, Universidad Andrés Bello, Santiago 8370186, Chile; [email protected] 4 Vancouver Prostate Centre, Vancouver, BC V6Z 1Y6, Canada; [email protected] 5 Department of Urological Sciences, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada 6 Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago 7560484, Chile 7 Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile 8 Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile * Correspondence: [email protected] These authors contributed equally to this work. y Received: 4 November 2020; Accepted: 1 December 2020; Published: 4 December 2020 Abstract: The transient receptor potential melastatin (TRPM) subfamily belongs to the TRP cation channels family. Since the first cloning of TRPM1 in 1989, tremendous progress has been made in identifying novel members of the TRPM subfamily and their functions. The TRPM subfamily is composed of eight members consisting of four six-transmembrane domain subunits, resulting in homomeric or heteromeric channels.
    [Show full text]