title: Photochemical activation of TRPA1 channels in neurons and animals.
abstract: Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild-type zebrafish and mice. To our surprise, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in nontransgenic animals, including humans.
authors: Department of Medicine, Cardiovascular Research Center and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA. dkokel@cvrc.mgh.harvard.edu
authors: David
authors: D
authors: Kokel
authors: Chung Yan J
authors: CY
authors: Cheung
authors: Robert
authors: R
authors: Mills
authors: Jaeda
authors: J
authors: Coutinho-Budd
authors: Liyi
authors: L
authors: Huang
authors: Vincent
authors: V
authors: Setola
authors: Jared
authors: J
authors: Sprague
authors: Shan
authors: S
authors: Jin
authors: Youngnam N
authors: YN
authors: Jin
authors: Xi-Ping
authors: XP
authors: Huang
authors: Giancarlo
authors: G
authors: Bruni
authors: Clifford J
authors: CJ
authors: Woolf
authors: Bryan L
authors: BL
authors: Roth
authors: Michael R
authors: MR
authors: Hamblin
authors: Mark J
authors: MJ
authors: Zylka
authors: David J
authors: DJ
authors: Milan
authors: Randall T
authors: RT
authors: Peterson
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000528:radiation effects; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects / Q000528:radiation effects; D004625:Embryo, Nonmammalian; D006801:Humans; D007473:Ion Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D007834:Lasers; D008027:Light; D055537:Light Signal Transduction / Q000187:drug effects* / Q000528:radiation effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D009154:Mutation; D010084:Oxidation-Reduction; D055668:Photochemical Processes / Q000187:drug effects* / Q000528:radiation effects; D010879:Piperazines / Q000494:pharmacology; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D007473:Ion Channels; D010879:Piperazines; D020033:Protein Isoforms; D054852:Small Molecule Libraries; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; D029961:Zebrafish Proteins; C494579:trpa1a protein, zebrafish; D003545:Cysteine; C007306:triethylenediamine
references: Antimicrob Agents Chemother. 2006 Apr;50(4):1402-10
references: 16569858
references: Br J Pharmacol Chemother. 1963 Feb;20:106-20
references: 14023050
references: Nat Neurosci. 2004 Dec;7(12):1381-6
references: 15558062
references: Nat Neurosci. 2011 Jan;14(1):22-4
references: 21131952
references: Curr Opin Neurobiol. 2004 Jun;14(3):362-9
references: 15194117
references: J Comp Neurol. 1999 Feb 22;404(4):515-36
references: 9987995
references: J Physiol. 2011 May 15;589(Pt 10):2447-57
references: 21486811
references: Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5163-8
references: 17360345
references: Nat Methods. 2008 Apr;5(4):331-8
references: 18311146
references: Nature. 2007 Feb 1;445(7127):541-5
references: 17237762
references: Chem Biol. 2003 Oct;10(10):901-8
references: 14583256
references: Science. 2010 Jan 15;327(5963):348-51
references: 20075256
references: Nat Chem Biol. 2006 Jan;2(1):47-52
references: 16408092
references: Nat Chem Biol. 2012 Apr 01;8(5):471-6
references: 22466421
references: Nat Neurosci. 2010 Aug;13(8):1027-32
references: 20581843
references: J Am Chem Soc. 2007 Jan 17;129(2):260-1
references: 17212390
references: Neuron. 2007 May 24;54(4):535-45
references: 17521567
references: Subcell Biochem. 2007;45:253-71
references: 18193640
references: Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8752-6
references: 8090718
references: Nat Rev Drug Discov. 2005 Jan;4(1):35-44
references: 15688071
references: Nano Lett. 2007 Dec;7(12):3859-63
references: 18034506
references: Phys Chem Chem Phys. 2009 Jan 7;11(1):133-41
references: 19081916
references: Mol Pain. 2008 Oct 27;4:48
references: 18954467
references: Neuron. 2004 Mar 25;41(6):849-57
references: 15046718
references: Nat Neurosci. 2005 Sep;8(9):1263-8
references: 16116447
references: J Neurosci. 2008 Oct 1;28(40):10102-10
references: 18829968
references: Neuron. 2006 Apr 20;50(2):277-89
references: 16630838
references: Neuron. 2009 Jul 16;63(1):27-39
references: 19607790
references: Nat Rev Microbiol. 2011 Aug 08;9(10):713-23
references: 21822294
references: Nat Methods. 2011 Jan;8(1):26-9
references: 21191368
references: Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19564-8
references: 17164327
references: Annu Rev Neurosci. 2006;29:135-61
references: 16776582
references: Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7661-5
references: 7689225
references: J Neurophysiol. 2011 Jul;106(1):488-96
references: 21525363
references: Nat Chem Biol. 2011 Aug 28;7(10):701-11
references: 21873995
references: Nat Chem Biol. 2010 Mar;6(3):231-237
references: 20081854
references: J Med Chem. 2011 Feb 10;54(3):788-808
references: 21218783
references: Neuron. 2010 Jun 10;66(5):671-80
references: 20547126
references: Science. 1994 Jul 8;265(5169):255-8
references: 7912852
references: Gastroenterology. 2011 Apr;140(4):1283-1291.e1-2
references: 21185837
references: J Biol Chem. 2008 Aug 29;283(35):24136-44
references: 18550530
references: Ann N Y Acad Sci. 2011 Dec;1245:36-7
references: 22211974
references: Biochimie. 1986 Jun;68(6):771-8
references: 3019431
references: Curr Opin Neurobiol. 2009 Oct;19(5):544-52
references: 19828309
references: Nat Methods. 2012 Feb 19;9(4):396-402
references: 22343342