A Genome-Wide RNAi Screen in Caenorhabditis elegans Identifies the Nicotinic Acetylcholine Receptor Subunit ACR-7 as an Antipsychotic Drug Target

PLoS Genetics

Volumn 9, Issue 2, 2013, Pages

  Saur, Taixiang ^a,b   DeMarco, Sarah E ^b   Ortiz, Angelica ^c   Sliwoski, Gregory R ^d   Hao, Limin ^a,b   Wang, Xin ^a,b   Cohen, Bruce M ^a,b   Buttner, Edgar A ^a,b  

^a HARVARD MEDICAL SCHOOL   (United States)

^b MCLEAN HOSPITAL   (United States)

^c UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^d VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BUNGAROTOXIN RECEPTOR; CLOZAPINE; GREEN FLUORESCENT PROTEIN; HYBRID PROTEIN; LEVAMISOLE; NICOTINE;

ACR 7 GENE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CAENORHABDITIS ELEGANS; CHA 1 GENE; CONCENTRATION RESPONSE; CONTROLLED STUDY; DEVELOPMENTAL TOXICITY; DRUG SCREENING; DRUG TARGETING; GENE; GENE INACTIVATION; GENE MUTATION; GENETIC ASSOCIATION; GENETIC SCREENING; LARVAL STAGE; NONHUMAN; PHARMACOLOGICAL STIMULATION; PHARYNGEAL MUSCLE; PHENOTYPE; PSYCHOPHARMACOLOGY; RNA INTERFERENCE; SCLA GENE; TETANY; UNC 17 GENE;

ANIMALS; ANTIPSYCHOTIC AGENTS; BIOMARKERS, PHARMACOLOGICAL; CAENORHABDITIS ELEGANS; CLOZAPINE; GENE KNOCKOUT TECHNIQUES; GENOME; HUMANS; LARVA; MOLECULAR TARGETED THERAPY; NICOTINIC AGONISTS; RECEPTORS, NICOTINIC; RNA INTERFERENCE; SIGNAL TRANSDUCTION;

EID: 84874762077     PISSN: 15537390     EISSN: 15537404     Source Type: Journal    
DOI: 10.1371/journal.pgen.1003313     Document Type: Article

References (67)

1. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, et al. (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353: 1209-1223.
2. Agid O, Foussias G, Singh S, Remington G, (2010) Where to position clozapine: re examining the evidence. Can J Psychiatry 55: 677-684.
3. McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, et al. (2006) Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 163: 600-610.
4. Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, et al. (2003) Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 60: 82-91.
5. Gray JA, Roth BL, (2007) The pipeline and future of drug development in schizophrenia. Mol Psychiatry 12: 904-922.
6. Meltzer HY, (2004) What's atypical about atypical antipsychotic drugs? Curr Opin Pharmacol 4: 53-57.
7. Dranovsky A, Hen R, (2006) Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry 59: 1136-1143.
8. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, et al. (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301: 805-809.
9. Burne T, Scott E, van Swinderen B, Hilliard M, Reinhard J, et al. (2011) Big ideas for small brains: what can psychiatry learn from worms, flies, bees and fish? Mol Psychiatry 16: 7-16.
10. Wang X, Sliwoski GR, Buttner EA, (2011) The relevance of Caenorhabditis elegans genetics for understanding human psychiatric disease. Harv Rev Psychiatry 19: 210-218.
11. Karmacharya R, Lynn SK, Demarco S, Ortiz A, Wang X, et al. (2011) Behavioral effects of clozapine: involvement of trace amine pathways in C. elegans and M. musculus. Brain Res 1393: 91-99.
12. Karmacharya R, Sliwoski GR, Lundy MY, Suckow RF, Cohen BM, et al. (2009) Clozapine interaction with phosphatidyl inositol 3-kinase (PI3K)/insulin-signaling pathway in Caenorhabditis elegans. Neuropsychopharmacology 34: 1968-1978.
13. Weeks KR, Dwyer DS, Aamodt EJ, (2011) Clozapine and lithium require Caenorhabditis elegans beta-arrestin and serum- and glucocorticoid-inducible kinase to affect Daf-16 (FOXO) localization. J Neurosci Res 89: 1658-1665.
14. Weeks KR, Dwyer DS, Aamodt EJ, (2010) Antipsychotic drugs activate the C. elegans Akt pathway via the DAF-2 insulin/IGF-1 receptor. ACS Chem Neurosci 1: 463-473.
15. Harrison PJ, Weinberger DR, (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10: 40-68.
16. Jones CK, Byun N, Bubser M, (2012) Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia. Neuropsychopharmacology 37: 16-42.
17. Martin LF, Freedman R, (2007) Schizophrenia and the alpha7 nicotinic acetylcholine receptor. Int Rev Neurobiol 78: 225-246.
18. Ericson E, Gebbia M, Heisler LE, Wildenhain J, Tyers M, et al. (2008) Off-target effects of psychoactive drugs revealed by genome-wide assays in yeast. PLoS Genet 4: e1000151 doi:10.1371/journal.pgen.1000151.
19. Donohoe DR, Jarvis RA, Weeks K, Aamodt EJ, Dwyer DS, (2009) Behavioral adaptation in C. elegans produced by antipsychotic drugs requires serotonin and is associated with calcium signaling and calcineurin inhibition. Neurosci Res 64: 280-289.
20. Donohoe DR, Aamodt EJ, Osborn E, Dwyer DS, (2006) Antipsychotic drugs disrupt normal development in Caenorhabditis elegans via additional mechanisms besides dopamine and serotonin receptors. Pharmacol Res 54: 361-372.
21. Kamath RS, Ahringer J, (2003) Genome-wide RNAi screening in Caenorhabditis elegans. Methods 30: 313-321.
22. Simmer F, Moorman C, van der Linden AM, Kuijk E, van den Berghe PV, et al. (2003) Genome-wide RNAi of C. elegans using the hypersensitive rrf-3 strain reveals novel gene functions. PLoS Biol 1: e12 doi:10.1371/journal.pbio.0000012.
23. Harada H, Kurauchi M, Hayashi R, Eki T, (2007) Shortened lifespan of nematode Caenorhabditis elegans after prolonged exposure to heavy metals and detergents. Ecotoxicol Environ Saf 66: 378-383.
24. Kondo M, Yanase S, Ishii T, Hartman PS, Matsumoto K, et al. (2005) The p38 signal transduction pathway participates in the oxidative stress-mediated translocation of DAF-16 to Caenorhabditis elegans nuclei. Mech Ageing Dev 126: 642-647.
25. Lee W, Lee TH, Park BJ, Chang JW, Yu JR, et al. (2005) Caenorhabditis elegans calnexin is N-glycosylated and required for stress response. Biochem Biophys Res Commun 338: 1018-1030.
26. Struwe WB, Hughes BL, Osborn DW, Boudreau ED, Shaw KM, et al. (2009) Modeling a congenital disorder of glycosylation type I in C. elegans: a genome-wide RNAi screen for N-glycosylation-dependent loci. Glycobiology 19: 1554-1562.
27. Kamath RS, Fraser AG, Dong Y, Poulin G, Durbin R, et al. (2003) Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421: 231-237.
28. Jones AK, Davis P, Hodgkin J, Sattelle DB, (2007) The nicotinic acetylcholine receptor gene family of the nematode Caenorhabditis elegans: an update on nomenclature. Invert Neurosci 7: 129-131.
29. Jones AK, Sattelle DB, (2004) Functional genomics of the nicotinic acetylcholine receptor gene family of the nematode, Caenorhabditis elegans. Bioessays 26: 39-49.
30. Albuquerque EX, Pereira EF, Alkondon M, Rogers SW, (2009) Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 89: 73-120.
31. Fucile S, (2004) Ca2+ permeability of nicotinic acetylcholine receptors. Cell Calcium 35: 1-8.
32. Boulin T, Gielen M, Richmond JE, Williams DC, Paoletti P, et al. (2008) Eight genes are required for functional reconstitution of the Caenorhabditis elegans levamisole sensitive acetylcholine receptor. Proc Natl Acad Sci U S A 105: 18590-18595.
33. Jospin M, Qi YB, Stawicki TM, Boulin T, Schuske KR, et al. (2009) A neuronal acetylcholine receptor regulates the balance of muscle excitation and inhibition in Caenorhabditis elegans. PLoS Biol 7: e1000265 doi:10.1371/journal.pbio.1000265.
34. Community TCeR (2011) Wormbase web site, release WS227.
35. Alfonso A, Grundahl K, Duerr JS, Han HP, Rand JB, (1993) The Caenorhabditis elegans unc-17 gene: a putative vesicular acetylcholine transporter. Science 261: 617-619.
36. Rand JB, Russell RL, (1984) Choline acetyltransferase-deficient mutants of the nematode Caenorhabditis elegans. Genetics 106: 227-248.
37. Raizen DM, Lee RY, Avery L, (1995) Interacting genes required for pharyngeal excitation by motor neuron MC in Caenorhabditis elegans. Genetics 141: 1365-1382.
38. Rand JB, (2007) Wormbook: Acetylcholine.
39. Sur C, Mallorga PJ, Wittmann M, Jacobson MA, Pascarella D, et al. (2003) N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc Natl Acad Sci U S A 100: 13674-13679.
40. Costa LG, Steardo L, Cuomo V, (2004) Structural effects and neurofunctional sequelae of developmental exposure to psychotherapeutic drugs: experimental and clinical aspects. Pharmacol Rev 56: 103-147.
41. Page AP, Johnstone IL, (2007) Wormbook: The cuticle.
42. Baldessarini RJ, Centorrino F, Flood JG, Volpicelli SA, Huston-Lyons D, et al. (1993) Tissue concentrations of clozapine and its metabolites in the rat. Neuropsychopharmacology 9: 117-124.
43. Centorrino F, Baldessarini RJ, Frankenburg FR, Kando J, Volpicelli SA, et al. (1996) Serum levels of clozapine and norclozapine in patients treated with selective serotonin reuptake inhibitors. Am J Psychiatry 153: 820-822.
44. Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, et al. (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320: 539-543.
45. Walsh MT, Ryan M, Hillmann A, Condren R, Kenny D, et al. (2002) Elevated expression of integrin alpha(IIb) beta(IIIa) in drug-naive, first-episode schizophrenic patients. Biol Psychiatry 52: 874-879.
46. Wang Z, Wei J, Zhang X, Guo Y, Xu Q, et al. (2006) A review and re-evaluation of an association between the NOTCH4 locus and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 141B: 902-906.
47. Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, et al. (2001) alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block A beta amyloid-induced neurotoxicity. J Biol Chem 276: 13541-13546.
48. Thomas DR, Dada A, Jones GA, Deisz RA, Gigout S, et al. (2010) N-desmethylclozapine (NDMC) is an antagonist at the human native muscarinic M(1) receptor. Neuropharmacology 58: 1206-1214.
49. Francis MM, Cheng EY, Weiland GA, Oswald RE, (2001) Specific activation of the alpha 7 nicotinic acetylcholine receptor by a quaternary analog of cocaine. Mol Pharmacol 60: 71-79.
50. Mobascher A, Winterer G, (2008) The molecular and cellular neurobiology of nicotine abuse in schizophrenia. Pharmacopsychiatry 41 (Suppl 1):: S51-59.
51. Freedman R, Adams CE, Leonard S, (2000) The alpha7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia. J Chem Neuroanat 20: 299-306.
52. Freedman R, Hall M, Adler LE, Leonard S, (1995) Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 38: 22-33.
53. Martin-Ruiz CM, Haroutunian VH, Long P, Young AH, Davis KL, et al. (2003) Dementia rating and nicotinic receptor expression in the prefrontal cortex in schizophrenia. Biol Psychiatry 54: 1222-1233.
54. Marutle A, Zhang X, Court J, Piggott M, Johnson M, et al. (2001) Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia. J Chem Neuroanat 22: 115-126.
55. Grinevich VP, Papke RL, Lippiello PM, Bencherif M, (2009) Atypical antipsychotics as noncompetitive inhibitors of alpha4beta2 and alpha7 neuronal nicotinic receptors. Neuropharmacology 57: 183-191.
56. Singhal SK, Zhang L, Morales M, Oz M, (2007) Antipsychotic clozapine inhibits the function of alpha7-nicotinic acetylcholine receptors. Neuropharmacology 52: 387-394.
57. Ballivet M, Alliod C, Bertrand S, Bertrand D, (1996) Nicotinic acetylcholine receptors in the nematode Caenorhabditis elegans. J Mol Biol 258: 261-269.
58. Raymond V, Mongan NP, Sattelle DB, (2000) Anthelmintic actions on homomer forming nicotinic acetylcholine receptor subunits: chicken alpha7 and ACR-16 from the nematode Caenorhabditis elegans. Neuroscience 101: 785-791.
59. Simosky JK, Stevens KE, Adler LE, Freedman R, (2003) Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism. Psychopharmacology (Berl) 165: 386-396.
60. Feng Z, Li W, Ward A, Piggott BJ, Larkspur ER, et al. (2006) A C. elegans model of nicotine-dependent behavior: regulation by TRP-family channels. Cell 127: 621-633.
61. Gotti C, Clementi F, Fornari A, Gaimarri A, Guiducci S, et al. (2009) Structural and functional diversity of native brain neuronal nicotinic receptors. Biochem Pharmacol 78: 703-711.
62. Wang N, Orr-Urtreger A, Chapman J, Ergun Y, Rabinowitz R, et al. (2005) Hidden function of neuronal nicotinic acetylcholine receptor beta2 subunits in ganglionic transmission: comparison to alpha5 and beta4 subunits. J Neurol Sci 228: 167-177.
63. Wang F, Gerzanich V, Wells GB, Anand R, Peng X, et al. (1996) Assembly of human neuronal nicotinic receptor alpha5 subunits with alpha3, beta2, and beta4 subunits. J Biol Chem 271: 17656-17665.
64. Yu CR, Role LW, (1998) Functional contribution of the alpha5 subunit to neuronal nicotinic channels expressed by chick sympathetic ganglion neurones. J Physiol 509 (Pt 3) (): 667-681.
65. Yu CR, Role LW, (1998) Functional contribution of the alpha7 subunit to multiple subtypes of nicotinic receptors in embryonic chick sympathetic neurones. J Physiol 509 (Pt 3) (): 651-665.
66. Nollen EA, Garcia SM, van Haaften G, Kim S, Chavez A, et al. (2004) Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc Natl Acad Sci U S A 101: 6403-6408.
67. Mello CC, Kramer JM, Stinchcomb D, Ambros V, (1991) Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J 10: 3959-3970.