The Role of Transient Receptor Potential Cation Channels in Ca2þ Signaling
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The Two-Pore Channel TPCN2 Mediates NAADP-Dependent Ca2+-Release from Lysosomal Stores
Pflugers Arch - Eur J Physiol (2009) 458:891–899 DOI 10.1007/s00424-009-0690-y ION CHANNELS, RECEPTORS AND TRANSPORTERS The two-pore channel TPCN2 mediates NAADP-dependent Ca2+-release from lysosomal stores Xiangang Zong & Michael Schieder & Hartmut Cuny & Stefanie Fenske & Christian Gruner & Katrin Rötzer & Oliver Griesbeck & Hartmann Harz & Martin Biel & Christian Wahl-Schott Received: 30 May 2009 /Accepted: 2 June 2009 /Published online: 26 June 2009 # The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Second messenger-induced Ca2+-release from show that TPCN2, a novel member of the two-pore cation intracellular stores plays a key role in a multitude channel family, displays the basic properties of native of physiological processes. In addition to 1,4,5-inositol NAADP-dependent Ca2+-release channels. TPCN2 tran- 2+ trisphosphate (IP3), Ca , and cyclic ADP ribose (cADPR) scripts are widely expressed in the body and encode a that trigger Ca2+-release from the endoplasmatic reticulum lysosomal protein forming homomers. TPCN2 mediates (ER), nicotinic acid adenine dinucleotide phosphate intracellular Ca2+-release after activation with low- (NAADP) has been identified as a cellular metabolite that nanomolar concentrations of NAADP while it is desensitized mediates Ca2+-release from lysosomal stores. While by micromolar concentrations of this second messenger and NAADP-induced Ca2+-release has been found in many is insensitive to the NAADP analog nicotinamide adenine tissues and cell types, the molecular identity of the channel dinucleotide phosphate (NADP). Furthermore, TPCN2- (s) conferring this release remained elusive so far. Here, we mediated Ca2+-release is almost completely abolished when the capacity of lysosomes for storing Ca2+ is pharmacolog- 2+ Xiangang Zong and Michael Schieder contributed equally to this work. -
Chapter Four – TRPA1 Channels: Chemical and Temperature Sensitivity
CHAPTER FOUR TRPA1 Channels: Chemical and Temperature Sensitivity Willem J. Laursen1,2, Sviatoslav N. Bagriantsev1,* and Elena O. Gracheva1,2,* 1Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA 2Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT, USA *Corresponding author: E-mail: [email protected], [email protected] Contents 1. Introduction 90 2. Activation and Regulation of TRPA1 by Chemical Compounds 91 2.1 Chemical activation of TRPA1 by covalent modification 91 2.2 Noncovalent activation of TRPA1 97 2.3 Receptor-operated activation of TRPA1 99 3. Temperature Sensitivity of TRPA1 101 3.1 TRPA1 in mammals 101 3.2 TRPA1 in insects and worms 103 3.3 TRPA1 in fish, birds, reptiles, and amphibians 103 3.4 TRPA1: Molecular mechanism of temperature sensitivity 104 Acknowledgments 107 References 107 Abstract Transient receptor potential ankyrin 1 (TRPA1) is a polymodal excitatory ion channel found in sensory neurons of different organisms, ranging from worms to humans. Since its discovery as an uncharacterized transmembrane protein in human fibroblasts, TRPA1 has become one of the most intensively studied ion channels. Its function has been linked to regulation of heat and cold perception, mechanosensitivity, hearing, inflam- mation, pain, circadian rhythms, chemoreception, and other processes. Some of these proposed functions remain controversial, while others have gathered considerable experimental support. A truly polymodal ion channel, TRPA1 is activated by various stimuli, including electrophilic chemicals, oxygen, temperature, and mechanical force, yet the molecular mechanism of TRPA1 gating remains obscure. In this review, we discuss recent advances in the understanding of TRPA1 physiology, pharmacology, and molecular function. -
Disease-Associated Mutations in TRPM3 Render the Channel Overactive Via Two Distinct Mechanisms
bioRxiv preprint doi: https://doi.org/10.1101/2020.04.20.052167; this version posted April 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Disease-associated mutations in TRPM3 render the channel overactive via two distinct mechanisms Siyuan Zhao, Yevgen Yudin, Tibor Rohacs Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ ABSTRACT Transient Receptor Potential Melastatin 3 (TRPM3) is a Ca2+ permeable non-selective cation channel activated by heat and chemical agonists such as pregnenolone sulfate and CIM0216. TRPM3 mutations in humans were recently reported to be associated with intellectual disability and epilepsy; the functional effects of those mutations however were not reported. Here we show that both disease-associated mutations of TRPM3 render the channel overactive, but likely via different mechanisms. The Val to Met substitution in the S4-S5 loop induced a larger increase in basal activity and agonist sensitivity at room temperature than the Pro to Gln substitution in the extracellular segment of S6. In contrast, heat activation was increased more by the S6 mutant than by the S4-S5 segment mutant. Both mutants were inhibited by the TRPM3 antagonist primidone, suggesting a potential therapeutic intervention to treat this disease. INTRODUCTION Transient Receptor Potential Melastatin 3 (TRPM3) is a Ca2+ permeable, non-selective cation channel activated by heat (Vriens et al., 2011) and chemical activators such as the neurosteroid pregnenolone sulfate (PregS) (Wagner et al., 2008) and the synthetic compound CIM0216 (Held et al., 2015). -
Recessive Mutations of the Gene TRPM1 Abrogate on Bipolar Cell Function and Cause Complete Congenital Stationary Night Blindness in Humans
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REPORT Recessive Mutations of the Gene TRPM1 Abrogate ON Bipolar Cell Function and Cause Complete Congenital Stationary Night Blindness in Humans Zheng Li,1 Panagiotis I. Sergouniotis,1 Michel Michaelides,1,2 Donna S. Mackay,1 Genevieve A. Wright,2 Sophie Devery,2 Anthony T. Moore,1,2 Graham E. Holder,1,2 Anthony G. Robson,1,2 and Andrew R. Webster1,2,* Complete congenital stationary night blindness (cCSNB) is associated with loss of function of rod and cone ON bipolar cells in the mammalian retina. In humans, mutations in NYX and GRM6 have been shown to cause the condition. Through the analysis of a consan- guineous family and screening of nine additional pedigrees, we have identified three families with recessive mutations in the gene TRPM1 encoding transient receptor potential cation channel, subfamily M, member 1, also known as melastatin. A number of other variants of unknown significance were found. All patients had myopia, reduced central vision, nystagmus, and electroretinographic evidence of ON bipolar cell dysfunction. None had abnormalities of skin pigmentation, although other skin conditions were reported. RNA derived from human retina and skin was analyzed and alternate 50 exons were determined. The most 50 exon is likely to harbor an initiation codon, and the protein sequence is highly conserved across vertebrate species. These findings suggest an important role of this specific cation channel for the normal function of ON bipolar cells in the human retina. Congenital stationary night blindness (CSNB) is a group of of the gene encoding transient receptor potential cation genetically determined, nondegenerative disorders of the channel, subfamily M, member 1 (TRPM1 [MIM *603576]) retina associated with lifelong deficient vision in the dark has been discovered in the skin and retina of horses homo- and often nystagmus and myopia. -
Expression Profiling of Ion Channel Genes Predicts Clinical Outcome in Breast Cancer
UCSF UC San Francisco Previously Published Works Title Expression profiling of ion channel genes predicts clinical outcome in breast cancer Permalink https://escholarship.org/uc/item/1zq9j4nw Journal Molecular Cancer, 12(1) ISSN 1476-4598 Authors Ko, Jae-Hong Ko, Eun A Gu, Wanjun et al. Publication Date 2013-09-22 DOI http://dx.doi.org/10.1186/1476-4598-12-106 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Ko et al. Molecular Cancer 2013, 12:106 http://www.molecular-cancer.com/content/12/1/106 RESEARCH Open Access Expression profiling of ion channel genes predicts clinical outcome in breast cancer Jae-Hong Ko1, Eun A Ko2, Wanjun Gu3, Inja Lim1, Hyoweon Bang1* and Tong Zhou4,5* Abstract Background: Ion channels play a critical role in a wide variety of biological processes, including the development of human cancer. However, the overall impact of ion channels on tumorigenicity in breast cancer remains controversial. Methods: We conduct microarray meta-analysis on 280 ion channel genes. We identify candidate ion channels that are implicated in breast cancer based on gene expression profiling. We test the relationship between the expression of ion channel genes and p53 mutation status, ER status, and histological tumor grade in the discovery cohort. A molecular signature consisting of ion channel genes (IC30) is identified by Spearman’s rank correlation test conducted between tumor grade and gene expression. A risk scoring system is developed based on IC30. We test the prognostic power of IC30 in the discovery and seven validation cohorts by both Cox proportional hazard regression and log-rank test. -
Molecular Characterization of TRPA Subfamily Genes and Function in Temperature Preference in Tuta Absoluta (Meyrick) (Lepidoptera: Gelechiidae)
International Journal of Molecular Sciences Article Molecular Characterization of TRPA Subfamily Genes and Function in Temperature Preference in Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) Xiao-Di Wang 1, Ze-Kai Lin 1 , Shun-Xia Ji 1, Si-Yan Bi 1, Wan-Xue Liu 1, Gui-Fen Zhang 1, Fang-Hao Wan 1,2 and Zhi-Chuang Lü 1,* 1 State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China; [email protected] (X.-D.W.); [email protected] (Z.-K.L.); [email protected] (S.-X.J.); [email protected] (S.-Y.B.); [email protected] (W.-X.L.); [email protected] (G.-F.Z.); [email protected] (F.-H.W.) 2 Agricultural Genome Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China * Correspondence: [email protected]; Tel.: +86-10-8210-9572 Abstract: To reveal the mechanism of temperature preference in Tuta absoluta, one of the top 20 plant pests in the world, we cloned and identified TaTRPA1, TaPain, and TaPyx genes by RACE and bioinformatic analysis, and clarified their expression profiles during different development stages using real-time PCR, and revealed their function in preference temperature by RNAi. The full-length cDNA of TaPain was 3136 bp, with a 2865-bp open reading frame encoding a 259.89-kDa Citation: Wang, X.-D.; Lin, Z.-K.; Ji, protein; and the partial length cDNA of TaPyx was 2326-bp, with a 2025-bp open reading frame S.-X.; Bi, S.-Y.; Liu, W.-X.; Zhang, G.-F.; encoding a 193.16-kDa protein. -
A Two-Pore Channel Protein Required for Regulating Mtorc1 Activity On
Chang et al. BMC Biology (2020) 18:8 https://doi.org/10.1186/s12915-019-0735-4 RESEARCH ARTICLE Open Access A two-pore channel protein required for regulating mTORC1 activity on starvation Fu-Sheng Chang1, Yuntao Wang1, Phillip Dmitriev1, Julian Gross2, Antony Galione2 and Catherine Pears1* Abstract Background: Two-pore channels (TPCs) release Ca2+ from acidic intracellular stores and are implicated in a number of diseases, but their role in development is unclear. The social amoeba Dictyostelium discoideum proliferates as single cells that aggregate to form a multicellular organism on starvation. Starvation is sensed by the mTORC1 complex which, like TPC proteins, is found on acidic vesicles. Here, we address the role of TPCs in development and under starvation. Results: We report that disruption of the gene encoding the single Dictyostelium TPC protein, TPC2, leads to a delay in early development and prolonged growth in culture with delayed expression of early developmental genes, although a rapid starvation-induced increase in autophagy is still apparent. Ca2+ signals induced by extracellular cAMP are delayed in developing tpc2− cells, and aggregation shows increased sensitivity to weak bases, consistent with reduced acidity of the vesicles. In mammalian cells, the mTORC1 protein kinase has been proposed to suppress TPC channel opening. Here, we show a reciprocal effect as tpc2− cells show an increased level of phosphorylation of an mTORC1 substrate, 4E-BP1. mTORC1 inhibition reverses the prolonged growth and increases the efficiency of aggregation of tpc2− cells. Conclusion: TPC2 is required for efficient growth development transition in Dictyostelium and acts through modulation of mTORC1 activity revealing a novel mode of regulation. -
TRPM8 Channels and Dry Eye
UC Berkeley UC Berkeley Previously Published Works Title TRPM8 Channels and Dry Eye. Permalink https://escholarship.org/uc/item/2gz2d8s3 Journal Pharmaceuticals (Basel, Switzerland), 11(4) ISSN 1424-8247 Authors Yang, Jee Myung Wei, Edward T Kim, Seong Jin et al. Publication Date 2018-11-15 DOI 10.3390/ph11040125 Peer reviewed eScholarship.org Powered by the California Digital Library University of California pharmaceuticals Review TRPM8 Channels and Dry Eye Jee Myung Yang 1,2 , Edward T. Wei 3, Seong Jin Kim 4 and Kyung Chul Yoon 1,* 1 Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; [email protected] 2 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea 3 School of Public Health, University of California, Berkeley, CA 94720, USA; [email protected] 4 Department of Dermatology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; [email protected] * Correspondence: [email protected] Received: 17 September 2018; Accepted: 12 November 2018; Published: 15 November 2018 Abstract: Transient receptor potential (TRP) channels transduce signals of chemical irritation and temperature change from the ocular surface to the brain. Dry eye disease (DED) is a multifactorial disorder wherein the eyes react to trivial stimuli with abnormal sensations, such as dryness, blurring, presence of foreign body, discomfort, irritation, and pain. There is increasing evidence of TRP channel dysfunction (i.e., TRPV1 and TRPM8) in DED pathophysiology. Here, we review some of this literature and discuss one strategy on how to manage DED using a TRPM8 agonist. -
Methylome and Transcriptome Maps of Human Visceral and Subcutaneous
www.nature.com/scientificreports OPEN Methylome and transcriptome maps of human visceral and subcutaneous adipocytes reveal Received: 9 April 2019 Accepted: 11 June 2019 key epigenetic diferences at Published: xx xx xxxx developmental genes Stephen T. Bradford1,2,3, Shalima S. Nair1,3, Aaron L. Statham1, Susan J. van Dijk2, Timothy J. Peters 1,3,4, Firoz Anwar 2, Hugh J. French 1, Julius Z. H. von Martels1, Brodie Sutclife2, Madhavi P. Maddugoda1, Michelle Peranec1, Hilal Varinli1,2,5, Rosanna Arnoldy1, Michael Buckley1,4, Jason P. Ross2, Elena Zotenko1,3, Jenny Z. Song1, Clare Stirzaker1,3, Denis C. Bauer2, Wenjia Qu1, Michael M. Swarbrick6, Helen L. Lutgers1,7, Reginald V. Lord8, Katherine Samaras9,10, Peter L. Molloy 2 & Susan J. Clark 1,3 Adipocytes support key metabolic and endocrine functions of adipose tissue. Lipid is stored in two major classes of depots, namely visceral adipose (VA) and subcutaneous adipose (SA) depots. Increased visceral adiposity is associated with adverse health outcomes, whereas the impact of SA tissue is relatively metabolically benign. The precise molecular features associated with the functional diferences between the adipose depots are still not well understood. Here, we characterised transcriptomes and methylomes of isolated adipocytes from matched SA and VA tissues of individuals with normal BMI to identify epigenetic diferences and their contribution to cell type and depot-specifc function. We found that DNA methylomes were notably distinct between diferent adipocyte depots and were associated with diferential gene expression within pathways fundamental to adipocyte function. Most striking diferential methylation was found at transcription factor and developmental genes. Our fndings highlight the importance of developmental origins in the function of diferent fat depots. -
Cryo-EM Structure of the Polycystic Kidney Disease-Like Channel PKD2L1
ARTICLE DOI: 10.1038/s41467-018-03606-0 OPEN Cryo-EM structure of the polycystic kidney disease-like channel PKD2L1 Qiang Su1,2,3, Feizhuo Hu1,3,4, Yuxia Liu4,5,6,7, Xiaofei Ge1,2, Changlin Mei8, Shengqiang Yu8, Aiwen Shen8, Qiang Zhou1,3,4,9, Chuangye Yan1,2,3,9, Jianlin Lei 1,2,3, Yanqing Zhang1,2,3,9, Xiaodong Liu2,4,5,6,7 & Tingliang Wang1,3,4,9 PKD2L1, also termed TRPP3 from the TRPP subfamily (polycystic TRP channels), is involved 1234567890():,; in the sour sensation and other pH-dependent processes. PKD2L1 is believed to be a non- selective cation channel that can be regulated by voltage, protons, and calcium. Despite its considerable importance, the molecular mechanisms underlying PKD2L1 regulations are largely unknown. Here, we determine the PKD2L1 atomic structure at 3.38 Å resolution by cryo-electron microscopy, whereby side chains of nearly all residues are assigned. Unlike its ortholog PKD2, the pore helix (PH) and transmembrane segment 6 (S6) of PKD2L1, which are involved in upper and lower-gate opening, adopt an open conformation. Structural comparisons of PKD2L1 with a PKD2-based homologous model indicate that the pore domain dilation is coupled to conformational changes of voltage-sensing domains (VSDs) via a series of π–π interactions, suggesting a potential PKD2L1 gating mechanism. 1 Ministry of Education Key Laboratory of Protein Science, Tsinghua University, Beijing 100084, China. 2 School of Life Sciences, Tsinghua University, Beijing 100084, China. 3 Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China. 4 School of Medicine, Tsinghua University, Beijing 100084, China. -
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-/- -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase