The TRPP2-Dependent Channel of Renal Primary Cilia Also Requires TRPM3

Total Page：16

File Type：pdf, Size：1020Kb

The TRPP2-dependent channel of renal primary cilia also requires TRPM3 Steven J. Kleene1, Brian J. Siroky2, Julio A. Landero-Figueroa3, Bradley P. Dixon4, Nolan W. Pachciarz2, Lu Lu2, and Nancy K. Kleene1 1Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, Ohio; 2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; 3Department of Chemistry, University of Cincinnati, Cincinnati, Ohio; 4Renal Section, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado IntroductIon Primary cilia of renal epithelial cells express several members of the transient receptor potential (TRP) class of cation-conducting channel, including TRPC1, TRPM3, TRPM4, TRPP2, and TRPV4. Some cases of autosomal dominant polycystic kidney disease (ADPKD) are caused by defects in TRPP2 (also called polycystin-2, PC2, or PKD2). A large-conductance, TRPP2- dependent channel in renal cilia has been well described, but it is not known whether this channel includes any other protein subunits. Methods To study this question, we investigated the pharmacology of the TRPP2-dependent channel through electrical recordings from the cilia of mIMCD-3 cells, a murine cell line of renal epithelial origin, results The pharmacology was found to match that of TRPM3 channels. The ciliary TRPP2-dependent channel is known to be activated by depolarization and/or increasing cytoplasmic Ca2+. This activation was greatly enhanced by external pregnenolone sulfate, an agonist of TRPM3 channels. Pregnenolone sulfate did not change the current-voltage relation of the channel. CIM0216, another TRPM3 agonist, modestly increased the activity of the ciliary channels. The channels were effectively blocked by isosakuranetin, a specific inhibitor of TRPM3 channels. Knocking out TRPM3 by CRISPR/ Cas9 genome editing eliminated the ciliary channel. After knocking out TRPM3, TRPP2 protein was still evident in the cilia, so it is unlikely that the absence of functional ciliary channels results from a failure of trafficking. conclusIons The channel is both TRPM3-dependent and TRPP2-dependent, suggesting that it may include both types of subunit. The potential of pregnenolone sulfate as a therapeutic for cystic kidney disease should be considered..

Copy Link

Recommended publications

The Structural Basis for an On–Off Switch Controlling Gβγ-Mediated Inhibition of TRPM3 Channels
The structural basis for an on–off switch controlling Gβγ-mediated inhibition of TRPM3 channels Marc Behrendta,b,1,2, Fabian Grussc,1,3, Raissa Enzerotha,b, Sandeep Demblaa,b, Siyuan Zhaod, Pierre-Antoine Crassousd, Florian Mohra, Mieke Nysc, Nikolaos Lourose, Rodrigo Gallardoe,4, Valentina Zorzinif,5, Doris Wagnera, Anastassios Economou (Αναστάσιoς Οικoνόμoυ)f, Frederic Rousseaue, Joost Schymkowitze, Stephan E. Philippg, Tibor Rohacsd, Chris Ulensc,6, and Johannes Oberwinklera,b,6 aInstitut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, 35037 Marburg, Germany;bCenter for Mind, Brain and Behavior (CMBB), Philipps-Universität Marburg and Justus-Liebig-Universität Giessen, 35032 Marburg, Germany; cLaboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; dDepartment of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ 07103; eSwitch Laboratory, VIB Center for Brain and Disease Research, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; fLaboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium; and gExperimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, 66421 Homburg, Germany Edited by László Csanády, Semmelweis University, Budapest, Hungary, and accepted by Editorial Board Member David E. Clapham August 27, 2020 (received for review February 13, 2020) TRPM3 channels play important roles in the detection of noxious also subject to inhibition by activated μORsorotherGPCRs(6, heat and in inflammatory thermal hyperalgesia. The activity of 24–28), a process that has been shown to take place in peripheral these ion channels in somatosensory neurons is tightly regulated by endings of nociceptive neurons since locally applied μOR or μ βγ -opioid receptors through the signaling of G proteins, thereby GABA receptor agonists inhibit TRPM3-dependent pain (24–26).
[Show full text]
TRPC1 Regulates the Activity of a Voltage-Dependent Nonselective Cation Current in Hippocampal CA1 Neurons
cells Article TRPC1 Regulates the Activity of a Voltage-Dependent Nonselective Cation Current in Hippocampal CA1 Neurons 1, 1 1,2 1,3, Frauke Kepura y, Eva Braun , Alexander Dietrich and Tim D. Plant * 1 Pharmakologisches Institut, BPC-Marburg, Fachbereich Medizin, Philipps-Universität Marburg, Karl-von-Frisch-Straße 2, 35043 Marburg, Germany; [email protected] (F.K.); braune@staff.uni-marburg.de (E.B.); [email protected] (A.D.) 2 Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, 80336 München, Germany 3 Center for Mind, Brain and Behavior, Philipps-Universität Marburg, 35032 Marburg, Germany * Correspondence: plant@staff.uni-marburg.de; Tel.: +49-6421-28-65038 Present address: Institut für Bodenkunde und Pflanzenernährung/Institut für angewandte Ökologie, y Hochschule Geisenheim University, Von-Lade-Str. 1, 65366 Geisenheim, Germany. Received: 27 November 2019; Accepted: 14 February 2020; Published: 18 February 2020 Abstract: The cation channel subunit TRPC1 is strongly expressed in central neurons including neurons in the CA1 region of the hippocampus where it forms complexes with TRPC4 and TRPC5. To investigate the functional role of TRPC1 in these neurons and in channel function, we compared current responses to group I metabotropic glutamate receptor (mGluR I) activation and looked +/+ / for major differences in dendritic morphology in neurons from TRPC1 and TRPC1− − mice. mGluR I stimulation resulted in the activation of a voltage-dependent nonselective cation current in both genotypes. Deletion of TRPC1 resulted in a modification of the shape of the current-voltage relationship, leading to an inward current increase. In current clamp recordings, the percentage of neurons that responded to depolarization in the presence of an mGluR I agonist with a plateau / potential was increased in TRPC1− − mice.
[Show full text]
The TRPM4 Channel Inhibitor 9-Phenanthrol
W&M ScholarWorks Arts & Sciences Articles Arts and Sciences 2014 The TRPM4 channel inhibitor 9-phenanthrol R. Guinamard T. Hof C. A. Del Negro College of William and Mary Follow this and additional works at: https://scholarworks.wm.edu/aspubs Recommended Citation Guinamard, R., Hof, T., & Del Negro, C. A. (2014). The TRPM4 channel inhibitor 9‐phenanthrol. British Journal of Pharmacology, 171(7), 1600-1613. This Article is brought to you for free and open access by the Arts and Sciences at W&M ScholarWorks. It has been accepted for inclusion in Arts & Sciences Articles by an authorized administrator of W&M ScholarWorks. For more information, please contact [email protected]. British Journal of DOI:10.1111/bph.12582 www.brjpharmacol.org BJP Pharmacology REVIEW Correspondence Romain Guinamard, Groupe Signalisation, Electrophysiologie et Imagerie des Lésions The TRPM4 channel d’Ischémie/Reperfusion Myocardique, EA4650, Université de Caen Basse Normandie, inhibitor 9-phenanthrol Sciences D, Esplande de la Paix, CS 14032, 14032 Caen Cedex 5, R Guinamard1,2, T Hof1 and C A Del Negro2 France. E-mail: [email protected] ---------------------------------------------------------------- 1EA 4650, Groupe Signalisation, Electrophysiologie et Imagerie des Lésions d’Ischémie-Reperfusion Myocardique, UCBN, Normandie Université, Caen, France, 2Department Keywords 9-phenanthrol; TRPM4; of Applied Science, The College of William and Mary, Williamsburg, VA, USA calcium-activated non-selective cation channel; cardioprotection; NSCCa ---------------------------------------------------------------- Received 1 November 2013 Revised 17 December 2013 Accepted 8 January 2014 The phenanthrene-derivative 9-phenanthrol is a recently identiﬁed inhibitor of the transient receptor potential melastatin (TRPM) 4 channel, a Ca2+-activated non-selective cation channel whose mechanism of action remains to be determined.
[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]
Involvement of TRPC4 and 5 Channels in Persistent Firing in Hippocampal CA1 Pyramidal Cells
cells Article Involvement of TRPC4 and 5 Channels in Persistent Firing in Hippocampal CA1 Pyramidal Cells Alberto Arboit 1,2,3, Antonio Reboreda 1,4 and Motoharu Yoshida 1,3,4,5,* 1 German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany; [email protected] (A.A.); [email protected] (A.R.) 2 Otto-von-Guericke University, 39120 Magdeburg, Germany 3 Faculty of Psychology, Ruhr University Bochum (RUB), Universitätsstraße 150, 44801 Bochum, Germany 4 Leibniz Institute for Neurobiology (LIN), 39118 Magdeburg, Germany 5 Center for Behavioral Brain Sciences (CBBS), 39106 Magdeburg, Germany * Correspondence: [email protected] Received: 1 December 2019; Accepted: 1 February 2020; Published: 5 February 2020 Abstract: Persistent neural activity has been observed in vivo during working memory tasks, and supports short-term (up to tens of seconds) retention of information. While synaptic and intrinsic cellular mechanisms of persistent firing have been proposed, underlying cellular mechanisms are not yet fully understood. In vitro experiments have shown that individual neurons in the hippocampus and other working memory related areas support persistent firing through intrinsic cellular mechanisms that involve the transient receptor potential canonical (TRPC) channels. Recent behavioral studies demonstrating the involvement of TRPC channels on working memory make the hypothesis that TRPC driven persistent firing supports working memory a very attractive one. However, this view has been challenged by recent findings that persistent firing in vitro is unchanged in TRPC knock out (KO) mice. To assess the involvement of TRPC channels further, we tested novel and highly specific TRPC channel blockers in cholinergically induced persistent firing in mice CA1 pyramidal cells for the first time.
[Show full text]
Heteromeric TRP Channels in Lung Inflammation
cells Review Heteromeric TRP Channels in Lung Inflammation Meryam Zergane 1, Wolfgang M. Kuebler 1,2,3,4,5,* and Laura Michalick 1,2 1 Institute of Physiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; [email protected] (M.Z.); [email protected] (L.M.) 2 German Centre for Cardiovascular Research (DZHK), 10785 Berlin, Germany 3 German Center for Lung Research (DZL), 35392 Gießen, Germany 4 The Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada 5 Department of Surgery and Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada * Correspondence: [email protected] Abstract: Activation of Transient Receptor Potential (TRP) channels can disrupt endothelial bar- rier function, as their mediated Ca2+ influx activates the CaM (calmodulin)/MLCK (myosin light chain kinase)-signaling pathway, and thereby rearranges the cytoskeleton, increases endothelial permeability and thus can facilitate activation of inflammatory cells and formation of pulmonary edema. Interestingly, TRP channel subunits can build heterotetramers, whereas heteromeric TRPC1/4, TRPC3/6 and TRPV1/4 are expressed in the lung endothelium and could be targeted as a protec- tive strategy to reduce endothelial permeability in pulmonary inflammation. An update on TRP heteromers and their role in lung inflammation will be provided with this review. Keywords: heteromeric TRP assemblies; pulmonary inflammation; endothelial permeability; TRPC3/6; TRPV1/4; TRPC1/4 Citation: Zergane, M.; Kuebler, W.M.; Michalick, L. Heteromeric TRP Channels in Lung Inflammation. Cells 1. Introduction 2021, 10, 1654. https://doi.org Pulmonary microvascular endothelial cells are a key constituent of the blood air bar- /10.3390/cells10071654 rier that has to be extremely thin (<1 µm) to allow for rapid and efficient alveolo-capillary gas exchange.
[Show full text]
Structure of Full-Length Human TRPM4
Structure of full-length human TRPM4 Jingjing Duana,1, Zongli Lib,c,1, Jian Lid,e,1, Ana Santa-Cruza, Silvia Sanchez-Martineza, Jin Zhangd,2, and David E. Claphama,f,g,2 aHoward Hughes Medical Institute, Ashburn, VA 20147; bHoward Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; cDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; dSchool of Basic Medical Sciences, Nanchang University, Nanchang, 330031 Jiangxi, China; eDepartment of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536; fDepartment of Neurobiology, Harvard Medical School, Boston, MA 02115; and gDepartment of Cardiology, Boston Children’s Hospital, Boston, MA 02115 Contributed by David E. Clapham, January 25, 2018 (sent for review December 19, 2017; reviewed by Mark T. Nelson, Dejian Ren, and Thomas Voets) Transient receptor potential melastatin subfamily member 4 Structure of Human TRPM4 (TRPM4) is a widely distributed, calcium-activated, monovalent- Full-length human TRPM4 (1,214 residues) was expressed using selective cation channel. Mutations in human TRPM4 (hTRPM4) the BacMam expression system (Materials and Methods). The result in progressive familial heart block. Here, we report the + TRPM4 construct used for expression retained the key func- electron cryomicroscopy structure of hTRPM4 in a closed, Na - tional properties of the wild-type channel, such as permeability + + bound, apo state at pH 7.5 to an overall resolution of 3.7 Å. Five to Na and K and activation by intracellular calcium (Fig. S1A). partially hydrated sodium ions are proposed to occupy the center The protein, obtained in the absence of exogenous calcium ions, of the conduction pore and the entrance to the coiled-coil domain.
[Show full text]
Distribution Profiles of Transient Receptor Potential Melastatin-Related and Vanilloid-Related Channels in Prostatic Tissue in Rat
TRPM and TRPV in rat prostate DOI: 10.1111/j.1745-7262.2007.00291.x www.asiaandro.com .Original Article . Distribution profiles of transient receptor potential melastatin-related and vanilloid-related channels in prostatic tissue in rat Huai-Peng Wang*, Xiao-Yong Pu*, Xing-Huan Wang Department of Urology, Guangdong Provnicial People’s Hospital, Guangzhou 510080, China Abstract Aim: To investigate the expression and distribution of the members of the transient receptor potential (TRP) channel members of TRP melastatin (TRPM) and TRP vanilloid (TRPV) subfamilies in rat prostatic tissue. Methods: Pros- tate tissue was obtained from male Sprague-Dawley rats. Reverse transcription polymerase chain reaction (RT-PCR) and quantitative real-time polymerase chain reaction (PCR) were used to check the expression of all TRPM and TRPV channel members with specific primers. Immunohistochemistry staining for TRPM8 and TRPV1 were also per- formed in rat tissues. Results: TRPM2, TRPM3, TRPM4, TRPM6, TRPM7, TRPM8, TRPV2 and TRPV4 mRNA were detected in all rat prostatic tissues. Very weak signals for TRPM1, TRPV1 and TRPV3 were also detected. The mRNA of TRPM5, TRPV5 and TRPV6 were not detected in all RT-PCR experiments. Quantitative real-time RT-PCR showed that TRPM2, TRPM3, TRPM4, TRPM8, TRPV2 and TRPV4 were the most abundantly expressed TRPM and TRPV subtypes, respectively. Fluorescence immunohistochemistry indicated that TRPM8 and TRPV1 are highly expressed in both epithelial and smooth muscle cells. Conclusion: Our results demonstrate that mRNA or protein for TRPM1, TRPM2, TRPM3, TRPM4, TRPM6, TRPM7, TRPM8, TRPV1, TRPV2, TRPV3 and TRPV4 exist in rat prostatic tissue. The data presented here assists in elucidating the physiological function of TRPM and TRPV channels.
[Show full text]
Transient Receptor Potential Cation Channel, Subfamily C, Member 5 (TRPC5) Is a Cold-Transducer in the Peripheral Nervous System
Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system Katharina Zimmermanna,b,1,2, Jochen K. Lennerza,c,d,1,3, Alexander Heina,1,4, Andrea S. Linke, J. Stefan Kaczmareka,b, Markus Dellinga, Serdar Uysala, John D. Pfeiferc, Antonio Riccioa, and David E. Claphama,b,f,5 Departments of aCardiology, Manton Center for Orphan Disease, and bNeurobiology, Harvard Medical School, Boston, MA 02115; cDepartment of Pathology and Immunology, Washington University, St. Louis, MO, 63110; dDepartment of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, 02116; eDepartment of Physiology and Pathophysiology, University Erlangen, 91054 Erlangen, Germany; and fHoward Hughes Medical Institute, Harvard Medical School, Children’s Hospital Boston, Boston, MA 02115 Contributed by David E. Clapham, September 20, 2011 (sent for review August 9, 2011) Detection and adaptation to cold temperature is crucial to survival. affected perforce by temperature, even if driven solely by con- Cold sensing in the innocuous range of cold (>10–15 °C) in the ventional NaV and KV channels—but high Q10 channels are likely mammalian peripheral nervous system is thought to rely primarily suspects in encoding temperature changes. Although TRPM8 on transient receptor potential (TRP) ion channels, most notably (a menthol receptor) is generally considered the primary cold – the menthol receptor, TRPM8. Here we report that TRP cation sensor for innocuous cold (11 13), and TRPA1 participates in channel, subfamily C member 5 (TRPC5), but not TRPC1/TRPC5 het- noxious cold sensing (9, 10) (14), many cold-sensitive neurons eromeric channels, are highly cold sensitive in the temperature lack TRPM8 as well as TRPA1 (15).
[Show full text]
Promiscuous G-Protein-Coupled Receptor Inhibition of Transient Receptor Potential Melastatin 3 Ion Channels by Gβγ Subunits
7840 • The Journal of Neuroscience, October 2, 2019 • 39(40):7840–7852 Cellular/Molecular Promiscuous G-Protein-Coupled Receptor Inhibition of Transient Receptor Potential Melastatin 3 Ion Channels by G␤␥ Subunits X Omar Alkhatib,1 XRobson da Costa,1,2 XClive Gentry,1 XTalisia Quallo,1 Stefanie Mannebach,3 Petra Weissgerber,3 Marc Freichel,4,5 Stephan E. Philipp,3 XStuart Bevan,1 and XDavid A. Andersson1 1Wolfson Centre for Age-Related Diseases, King’s College London, London SE1 1UL, United Kingdom, 2School of Pharmacy, Universidade Federal do Rio de Janeiro, 21941-908 Rio de Janeiro, Brazil, 3Experimental and Clinical Pharmacology and Toxicology/Center for Molecular Signaling (PZMS), Saarland University, 66421 Homburg, Germany, 4Pharmacological Institute, Ruprecht-Karls-University Heidelberg, 69120 Heidelberg, Germany, and 5German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany Transient receptor potential melastatin 3 (TRPM3) is a nonselective cation channel that is inhibited by G␤␥ subunits liberated following ␣ ␤␥ ␣ activation of G i/o protein-coupled receptors. Here, we demonstrate that TRPM3 channels are also inhibited by G released from G s ␣ and G q. Activation of the Gs-coupled adenosine 2B receptor and the Gq-coupled muscarinic acetylcholine M1 receptor inhibited the activity of TRPM3 heterologously expressed in HEK293 cells. This inhibition was prevented when the G␤␥ sink ␤ARK1-ct (C terminus of ␤-adrenergic receptor kinase-1) was coexpressed with TRPM3. In neurons isolated from mouse dorsal root ganglion (DRG), native TRPM3 channels were inhibited by activating Gs-coupled prostaglandin-EP2 and Gq-coupled bradykinin B2 (BK2) receptors. The Gi/o inhibitor pertussis toxin and inhibitors of PKA and PKC had no effect on EP2- and BK2-mediated inhibition of TRPM3, demonstrating ␣ that the receptors did not act through G i/o or through the major protein kinases activated downstream of G-protein-coupled receptor (GPCR) activation.
[Show full text]
1 Structural Basis of TRPC4 Regulation by Calmodulin And
bioRxiv preprint doi: https://doi.org/10.1101/2020.06.30.180778; this version posted July 1, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Structural basis of TRPC4 regulation by calmodulin and pharmacological agents 2 3 Deivanayagabarathy Vinayagam1, Dennis Quentin1, Oleg Sitsel1, Felipe Merino1,2, Markus 4 Stabrin1, Oliver Hofnagel1, Maolin Yu3, Mark W. Ledeboer3, Goran Malojcic3, Stefan 5 Raunser1 6 7 1Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, 44227 8 Dortmund, Germany 9 2Current address: Department of Protein Evolution, Max Planck Institute for Developmental 10 Biology, 72076 Tübingen, Germany 11 3Goldfinch Bio, 215 First St, Cambridge, MA 02142, USA 12 Correspondence: [email protected] 13 14 15 ABSTRACT 16 Canonical transient receptor potential channels (TRPC) are involved in receptor-operated 17 and/or store-operated Ca2+ signaling. Inhibition of TRPCs by small molecules was shown to be 18 promising in treating renal diseases. In cells, the channels are regulated by calmodulin. 19 Molecular details of both calmodulin and drug binding have remained elusive so far. Here we 20 report structures of TRPC4 in complex with a pyridazinone-based inhibitor and a pyridazinone- 21 based activator and calmodulin. The structures reveal that both activator and inhibitor bind to 22 the same cavity of the voltage-sensing-like domain and allow us to describe how structural 23 changes from the ligand binding site can be transmitted to the central ion-conducting pore of 24 TRPC4.
[Show full text]
Role of the TRPV Channels in the Endoplasmic Reticulum Calcium Homeostasis
cells Review Role of the TRPV Channels in the Endoplasmic Reticulum Calcium Homeostasis Aurélien Haustrate 1,2, Natalia Prevarskaya 1,2 and V’yacheslav Lehen’kyi 1,2,* 1 Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologies, University of Lille, 59650 Villeneuve d’Ascq, France; [email protected] (A.H.); [email protected] (N.P.) 2 Univ. Lille, Inserm, U1003 – PHYCEL – Physiologie Cellulaire, F-59000 Lille, France * Correspondence: [email protected]; Tel.: +33-320-337-078 Received: 14 October 2019; Accepted: 21 January 2020; Published: 28 January 2020 Abstract: It has been widely established that transient receptor potential vanilloid (TRPV) channels play a crucial role in calcium homeostasis in mammalian cells. Modulation of TRPV channels activity can modify their physiological function leading to some diseases and disorders like neurodegeneration, pain, cancer, skin disorders, etc. It should be noted that, despite TRPV channels importance, our knowledge of the TRPV channels functions in cells is mostly limited to their plasma membrane location. However, some TRPV channels were shown to be expressed in the endoplasmic reticulum where their modulation by activators and/or inhibitors was demonstrated to be crucial for intracellular signaling. In this review, we have intended to summarize the poorly studied roles and functions of these channels in the endoplasmic reticulum. Keywords: TRPV channels; endoplasmic reticulum; calcium signaling 1. Introduction: TRPV Channels Subfamily Overview Functional TRPV channels are tetrameric complexes and can be both homo or hetero-tetrameric. They can be divided into two groups: TRPV1, TRPV2, TRPV3, and TRPV4 which are thermosensitive channels, and TRPV5 and TRPV6 channels as the second group.
[Show full text]