Photo of David E. Clapham,  MD, PhD

David E. Clapham, MD, PhD

Boston Children's Hospital

Boston Children's Hospital
Phone: (617) 919-2680
Fax: (617) 731-0787


dclapham@enders.tch.harvard.edu

David E. Clapham, MD, PhD

Boston Children's Hospital

EDUCATIONAL TITLES

  • Aldo R. Castaneda Professor of Cardiovascular, Neurobiology, Harvard Medical School
  • Aldo R. Castaneda Professor of Cardiovascular, Pediatrics, Harvard Medical School
  • Aldo R. Castaneda Professor of Cardiovascular Research, Howard Hughes Medical Institute, Boston Children's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

The Clapham laboratory discovers and elucidates the structure and function of ion channels, as well as their role in overall biology of the organism. Recently we identified ion channels in primary cilia that are linked to Hedgehog signaling, a target of cancer therapies. We employ patch clamp electrophysiology, advanced imaging, biochemistry, and genetic manipulation to identify the genes that encode ion channels and their associated proteins. We are currently investigating the following channels and transporters:

TRP channels (TRPC1,4,5; TRPV3, 4; TRPM6, TRPM7)

Voltage-gated proton channels (Hv1)

Mitochondrial channels (MCU and its subunits)

Mitochondrial transporters (Letm1)

Cilia channels (PKD and PKDL)

Osmosensitive chloride channels

Sperm-specific ion channels (CatSper, Slo3)

Publications

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  • Blair NT, Philipson BI, Richards PM, Doerner JF, Segura A, Silver WL, Clapham DE. Naturally Produced Defensive Alkenal Compounds Activate TRPA1. Chem. Senses 2016; 41:281-92. PubMed
  • Naylor CE, Bagnéris C, DeCaen PG, Sula A, Scaglione A, Clapham DE, Wallace BA. Molecular basis of ion permeability in a voltage-gated sodium channel. EMBO J 2016; 35:820-30. PubMed
  • Chaudhuri D, Artiga DJ, Abiria SA, Clapham DE. Mitochondrial calcium uniporter regulator 1 (MCUR1) regulates the calcium threshold for the mitochondrial permeability transition. Proc Natl Acad Sci U S A 2016; 113:E1872-80. PubMed
  • Cai X, Wang X, Clapham DE. Early evolution of the eukaryotic Ca2+ signaling machinery: conservation of the CatSper channel complex. Mol. Biol. Evol. 2014; 31:2735-40. PubMed
  • Bagnéris C, DeCaen PG, Naylor CE, Pryde DC, Nobeli I, Clapham DE, Wallace BA. Prokaryotic NavMs channel as a structural and functional model for eukaryotic sodium channel antagonism. Proc Natl Acad Sci U S A 2014; 111:8428-33. PubMed
  • Krapivinsky G, Krapivinsky L, Manasian Y, Clapham DE. The TRPM7 chanzyme is cleaved to release a chromatin-modifying kinase. Cell 2014; 157:1061-72. PubMed
  • Chung JJ, Shim SH, Everley RA, Gygi SP, Zhuang X, Clapham DE. Structurally distinct Ca(2+) signaling domains of sperm flagella orchestrate tyrosine phosphorylation and motility. Cell 2014; 157:808-22. PubMed
  • Kahle KT, Khanna A, Clapham DE, Woolf CJ. Therapeutic restoration of spinal inhibition via druggable enhancement of potassium-chloride cotransporter KCC2-mediated chloride extrusion in peripheral neuropathic pain. JAMA Neurol 2014. PubMed
  • Py BF, Jin M, Desai BN, Penumaka A, Zhu H, Kober M, Dietrich A, Lipinski MM, Henry T, Clapham DE, Yuan J. Caspase-11 controls interleukin-1β release through degradation of TRPC1. Cell Rep 2014; 6:1122-8. PubMed
  • Riccio A, Li Y, Tsvetkov E, Gapon S, Yao GL, Smith KS, Engin E, Rudolph U, Bolshakov VY, Clapham DE. Decreased anxiety-like behavior and Gαq/11-dependent responses in the amygdala of mice lacking TRPC4 channels. J Neurosci 2014; 34:3653-67. PubMed
  • Sancak Y, Markhard AL, Kitami T, Kovács-Bogdán E, Kamer KJ, Udeshi ND, Carr SA, Chaudhuri D, Clapham DE, Li AA, Calvo SE, Goldberger O, Mootha VK. EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 2013; 342:1379-82. PubMed
  • Delling M, DeCaen PG, Doerner JF, Febvay S, Clapham DE. Primary cilia are specialized calcium signalling organelles. Nature 2013; 504:311-4. PubMed
  • Carvacho I, Lee HC, Fissore RA, Clapham DE. TRPV3 channels mediate strontium-induced mouse-egg activation. Cell Rep 2013; 5:1375-86. PubMed
  • DeCaen PG, Delling M, Vien TN, Clapham DE. Direct recording and molecular identification of the calcium channel of primary cilia. Nature 2013; 504:315-8. PubMed
  • Zeng XH, Navarro B, Xia XM, Clapham DE, Lingle CJ. Simultaneous knockout of Slo3 and CatSper1 abolishes all alkalization- and voltage-activated current in mouse spermatozoa. J Gen Physiol 2013; 142:305-13. PubMed
  • Sah R, Mesirca P, Van den Boogert M, Rosen J, Mably J, Mangoni ME, Clapham DE. Ion channel-kinase TRPM7 is required for maintaining cardiac automaticity. Proc Natl Acad Sci U S A 2013; 110:E3037-46. PubMed
  • Mesirca P, Marger L, Toyoda F, Rizzetto R, Audoubert M, Dubel S, Torrente AG, Difrancesco ML, Muller JC, Leoni AL, Couette B, Nargeot J, Clapham DE, Wickman K, Mangoni ME. The G-protein-gated K+ channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation. J Gen Physiol 2013; 142:113-26. PubMed
  • Sah R, Mesirca P, Mason X, Gibson W, Bates-Withers C, Van den Boogert M, Chaudhuri D, Pu WT, Mangoni ME, Clapham DE. Timing of myocardial trpm7 deletion during cardiogenesis variably disrupts adult ventricular function, conduction, and repolarization. Circulation 2013; 128:101-14. PubMed
  • Jiang D, Zhao L, Clish CB, Clapham DE. Letm1, the mitochondrial Ca2+/H+ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf-Hirschhorn syndrome. Proc Natl Acad Sci U S A 2013; 110:E2249-54. PubMed
  • Miki K, Clapham DE. Rheotaxis guides mammalian sperm. Curr Biol 2013; 23:443-52. PubMed
  • Cang C, Zhou Y, Navarro B, Seo YJ, Aranda K, Shi L, Battaglia-Hsu S, Nissim I, Clapham DE, Ren D. mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state. Cell 2013; 152:778-90. PubMed
  • Chaudhuri D, Sancak Y, Mootha VK, Clapham DE. MCU encodes the pore conducting mitochondrial calcium currents. Elife 2013; 2:e00704. PubMed
  • Wang X, Zhang X, Dong XP, Samie M, Li X, Cheng X, Goschka A, Shen D, Zhou Y, Harlow J, Zhu MX, Clapham DE, Ren D, Xu H. TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes. Cell 2012; 151:372-83. PubMed
  • Ye L, Kleiner S, Wu J, Sah R, Gupta RK, Banks AS, Cohen P, Khandekar MJ, Boström P, Mepani RJ, Laznik D, Kamenecka TM, Song X, Liedtke W, Mootha VK, Puigserver P, Griffin PR, Clapham DE, Spiegelman BM. TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell 2012; 151:96-110. PubMed
  • Desai BN, Krapivinsky G, Navarro B, Krapivinsky L, Carter BC, Febvay S, Delling M, Penumaka A, Ramsey IS, Manasian Y, Clapham DE. Cleavage of TRPM7 releases the kinase domain from the ion channel and regulates its participation in Fas-induced apoptosis. Dev Cell 2012; 22:1149-62. PubMed
  • Zhang X, Ren W, DeCaen P, Yan C, Tao X, Tang L, Wang J, Hasegawa K, Kumasaka T, He J, Wang J, Clapham DE, Yan N. Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel. Nature 2012; 486:130-4. PubMed
  • Kaczmarek JS, Riccio A, Clapham DE. Calpain cleaves and activates the TRPC5 channel to participate in semaphorin 3A-induced neuronal growth cone collapse. Proc Natl Acad Sci U S A 2012; 109:7888-92. PubMed
  • Wu LJ, Wu G, Akhavan Sharif MR, Baker A, Jia Y, Fahey FH, Luo HR, Feener EP, Clapham DE. The voltage-gated proton channel Hv1 enhances brain damage from ischemic stroke. Nat Neurosci 2012; 15:565-73. PubMed
  • Jin J, Wu LJ, Jun J, Cheng X, Xu H, Andrews NC, Clapham DE. The channel kinase, TRPM7, is required for early embryonic development. Proc Natl Acad Sci U S A 2012; 109:E225-33. PubMed
  • Doerner JF, Febvay S, Clapham DE. Controlled delivery of bioactive molecules into live cells using the bacterial mechanosensitive channel MscL. Nat Commun 2012; 3:990. PubMed
  • Lishko PV, Kirichok Y, Ren D, Navarro B, Chung JJ, Clapham DE. The control of male fertility by spermatozoan ion channels. Annu Rev Physiol 2012; 74:453-75. PubMed
  • Stotz SC, Clapham DE. Anion-sensitive fluorophore identifies the Drosophila swell-activated chloride channel in a genome-wide RNA interference screen. PLoS ONE 2012; 7:e46865. PubMed
  • Cai X, Clapham DE. Ancestral Ca2+ signaling machinery in early animal and fungal evolution. Mol. Biol. Evol. 2012. PubMed
  • Clapham DE, Miller C. A thermodynamic framework for understanding temperature sensing by transient receptor potential (TRP) channels. Proc Natl Acad Sci U S A 2011; 108:19492-7. PubMed
  • Krapivinsky G, Krapivinsky L, Stotz SC, Manasian Y, Clapham DE. POST, partner of stromal interaction molecule 1 (STIM1), targets STIM1 to multiple transporters. Proc Natl Acad Sci U S A 2011; 108:19234-9. PubMed
  • Zimmermann K, Lennerz JK, Hein A, Link AS, Kaczmarek JS, Delling M, Uysal S, Pfeifer JD, Riccio A, Clapham DE. Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system. Proc Natl Acad Sci U S A 2011; 108:18114-9. PubMed
  • Navarro B, Miki K, Clapham DE. ATP-activated P2X2 current in mouse spermatozoa. Proc Natl Acad Sci U S A 2011; 108:14342-7. PubMed
  • Chung JJ, Navarro B, Krapivinsky G, Krapivinsky L, Clapham DE. A novel gene required for male fertility and functional CATSPER channel formation in spermatozoa. Nat Commun 2011; 2:153. PubMed
  • Bates-Withers C, Sah R, Clapham DE. TRPM7, the Mg(2+) inhibited channel and kinase. Adv Exp Med Biol 2011; 704:173-83. PubMed
  • Wu LJ, Sweet TB, Clapham DE. International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family. Pharmacol. Rev. 2010; 62:381-404. PubMed
  • Ramsey IS, Mokrab Y, Carvacho I, Sands ZA, Sansom MS, Clapham DE. An aqueous H+ permeation pathway in the voltage-gated proton channel Hv1. Nat Struct Mol Biol 2010; 17:869-75. PubMed
  • Febvay S, Marini DM, Belcher AM, Clapham DE. Targeted cytosolic delivery of cell-impermeable compounds by nanoparticle-mediated, light-triggered endosome disruption. Nano Lett 2010; 10:2211-9. PubMed
  • Cheng X, Jin J, Hu L, Shen D, Dong XP, Samie MA, Knoff J, Eisinger B, Liu ML, Huang SM, Caterina MJ, Dempsey P, Michael LE, Dlugosz AA, Andrews NC, Clapham DE, Xu H. TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation. Cell 2010; 141:331-43. PubMed
  • Jiang D, Zhao L, Clapham DE. Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science 2009; 326:144-7. PubMed
  • Zhou H, Clapham DE. Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development. Proc Natl Acad Sci U S A 2009; 106:15750-5. PubMed
  • Riccio A,Li Y,Moon J,Kim KS,Smith KS,Rudolph U,Gapon S,Yao GL,Tsvetkov E,Rodig SJ,Van't Veer A,Meloni EG,Carlezon WA Jr,Bolshakov VY,Clapham DE. Essential role for TRPC5 in amygdala function and fear-related behavior. Cell 2009; 137:761-72. PubMed
  • Ramsey IS,Ruchti E,Kaczmarek JS,Clapham DE. Hv1 proton channels are required for high-level NADPH oxidase-dependent superoxide production during the phagocyte respiratory burst. Proc Natl Acad Sci U S A 2009; 106:7642-7. PubMed
  • Blair NT,Kaczmarek JS,Clapham DE. Intracellular calcium strongly potentiates agonist-activated TRPC5 channels. J Gen Physiol 2009; 133:525-46. PubMed
  • Clapham DE. A STIMulus Package puts orai calcium channels to work. Cell 2009; 136:814-6. PubMed
  • Zimmermann K,Hein A,Hager U,Kaczmarek JS,Turnquist BP,Clapham DE,Reeh PW. Phenotyping sensory nerve endings in vitro in the mouse. Nat Protoc 2009; 4:174-96. PubMed
  • Oancea E,Vriens J,Brauchi S,Jun J,Splawski I,Clapham DE. TRPM1 forms ion channels associated with melanin content in melanocytes. Sci Signal 2009; 2:ra21. PubMed
  • Jin J,Desai BN,Navarro B,Donovan A,Andrews NC,Clapham DE. Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2+ homeostasis. Science 2008; 322:756-60. PubMed
  • Brauchi S,Krapivinsky G,Krapivinsky L,Clapham DE. TRPM7 facilitates cholinergic vesicle fusion with the plasma membrane. Proc Natl Acad Sci U S A 2008; 105:8304-8. PubMed
  • Rama S, Krapivinsky G, Clapham DE, Medina I. The MUPP1-SynGAPalpha protein complex does not mediate activity-induced LTP. Mol Cell Neurosci 2008; 38:183-8. PubMed
  • Musset B, Cherny VV, Morgan D, Okamura Y, Ramsey IS, Clapham DE, Decoursey TE. Detailed comparison of expressed and native voltage-gated proton channel currents. J Physiol 2008; 586:2477-86. PubMed
  • Stotz SC, Vriens J, Martyn D, Clardy J, Clapham DE. Citral sensing by TRANSient receptor potential channels in dorsal root ganglion neurons. PLoS ONE 2008; 3:e2082. PubMed
  • Cai X,Clapham DE. Evolutionary genomics reveals lineage-specific gene loss and rapid evolution of a sperm-specific ion channel complex: CatSpers and CatSperbeta. PLoS ONE 2008; 3:e3569. PubMed
  • Clapham DE. Calcium signaling. Cell 2007; 131:1047-58. PubMed
  • Fujinami S, Sato T, Trimmer JS, Spiller BW, Clapham DE, Krulwich TA, Kawagishi I, Ito M. The voltage-gated Na+ channel NaVBP co-localizes with methyl-accepting chemotaxis protein at cell poles of alkaliphilic Bacillus pseudofirmus OF4. Microbiology 2007; 153:4027-38. PubMed
  • Xu H, Delling M, Li L, Dong X, Clapham DE. Activating mutation in a mucolipin transient receptor potential channel leads to melanocyte loss in varitint-waddler mice. Proc Natl Acad Sci U S A 2007; 104:18321-6. PubMed
  • Liu J, Xia J, Cho KH, Clapham DE, Ren D. CatSperbeta, a novel transmembrane protein in the CatSper channel complex. J Biol Chem 2007; 282:18945-52. PubMed
  • Navarro B, Kirichok Y, Clapham DE. KSper, a pH-sensitive K+ current that controls sperm membrane potential. Proc Natl Acad Sci U S A 2007; 104:7688-92. PubMed
  • Clapham DE. SnapShot: mammalian TRP channels. Cell 2007; 129:220. PubMed
  • Qi H, Moran MM, Navarro B, Chong JA, Krapivinsky G, Krapivinsky L, Kirichok Y, Ramsey IS, Quill TA, Clapham DE. All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility. Proc Natl Acad Sci U S A 2007; 104:1219-23. PubMed
  • Xu H, Delling M, Jun JC, Clapham DE. Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels. Nat Neurosci 2006; 9:628-635. PubMed
  • Ramsey IS, Moran MM, Chong JA, Clapham DE. A voltage-gated proton-selective channel lacking the pore domain. Nature 2006; 440:1213-6. PubMed
  • Kirichok Y, Navarro B, Clapham DE. Whole-cell patch-clamp measurements of spermatozoa reveal an alkaline-activated Ca2+ channel. Nature 2006; 439:737-40. PubMed
  • Ramsey IS, Delling M, Clapham DE. An introduction to trp channels. Annu Rev Physiol 2006; 68:619-47. PubMed
  • Doerner JF, Delling M, Clapham DE. Ion channels and calcium signaling in motile cilia. Elife 2015. PubMed
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