title: An evolutionary conserved role for anaplastic lymphoma kinase in behavioral responses to ethanol.
abstract: Anaplastic lymphoma kinase (Alk) is a gene expressed in the nervous system that encodes a receptor tyrosine kinase commonly known for its oncogenic function in various human cancers. We have determined that Alk is associated with altered behavioral responses to ethanol in the fruit fly Drosophila melanogaster, in mice, and in humans. Mutant flies containing transposon insertions in dAlk demonstrate increased resistance to the sedating effect of ethanol. Database analyses revealed that Alk expression levels in the brains of recombinant inbred mice are negatively correlated with ethanol-induced ataxia and ethanol consumption. We therefore tested Alk gene knockout mice and found that they sedate longer in response to high doses of ethanol and consume more ethanol than wild-type mice. Finally, sequencing of human ALK led to the discovery of four polymorphisms associated with a low level of response to ethanol, an intermediate phenotype that is predictive of future alcohol use disorders (AUDs). These results suggest that Alk plays an evolutionary conserved role in ethanol-related behaviors. Moreover, ALK may be a novel candidate gene conferring risk for AUDs as well as a potential target for pharmacological intervention.
authors.affiliation: Department of Neurology, Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California, United States of America. alasek@gallo.ucsf.edu
authors.forename: Amy W
authors.initials: AW
authors.lastname: Lasek
authors.forename: Jana
authors.initials: J
authors.lastname: Lim
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Kliethermes
authors.forename: Karen H
authors.initials: KH
authors.lastname: Berger
authors.forename: Geoff
authors.initials: G
authors.lastname: Joslyn
authors.forename: Gerry
authors.initials: G
authors.lastname: Brush
authors.forename: Liquan
authors.initials: L
authors.lastname: Xue
authors.forename: Margaret
authors.initials: M
authors.lastname: Robertson
authors.forename: Monica S
authors.initials: MS
authors.lastname: Moore
authors.forename: Karen
authors.initials: K
authors.lastname: Vranizan
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Morris
authors.forename: Marc A
authors.initials: MA
authors.lastname: Schuckit
authors.forename: Raymond L
authors.initials: RL
authors.lastname: White
authors.forename: Ulrike
authors.initials: U
authors.lastname: Heberlein
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics; D057229:Alcoholics; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D016292:Procedural Sedation; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology*; D019143:Evolution, Molecular; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D011110:Polymorphism, Genetic / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*
chemical_list: C096249:Bx protein, Drosophila; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D000431:Ethanol; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases