title: DlgS97/SAP97, a neuronal isoform of discs large, regulates ethanol tolerance.
abstract: From a genetic screen for Drosophila melanogaster mutants with altered ethanol tolerance, we identified intolerant (intol), a novel allele of discs large 1 (dlg1). Dlg1 encodes Discs Large 1, a MAGUK (Membrane Associated Guanylate Kinase) family member that is the highly conserved homolog of mammalian PSD-95 and SAP97. The intol mutation disrupted specifically the expression of DlgS97, a SAP97 homolog, and one of two major protein isoforms encoded by dlg1 via alternative splicing. Expression of the major isoform, DlgA, a PSD-95 homolog, appeared unaffected. Ethanol tolerance in the intol mutant could be partially restored by transgenic expression of DlgS97, but not DlgA, in specific neurons of the fly's brain. Based on co-immunoprecipitation, DlgS97 forms a complex with N-methyl-D-aspartate (NMDA) receptors, a known target of ethanol. Consistent with these observations, flies expressing reduced levels of the essential NMDA receptor subunit dNR1 also showed reduced ethanol tolerance, as did mutants in the gene calcium/calmodulin-dependent protein kinase (caki), encoding the fly homolog of mammalian CASK, a known binding partner of DlgS97. Lastly, mice in which SAP97, the mammalian homolog of DlgS97, was conditionally deleted in adults failed to develop rapid tolerance to ethanol's sedative/hypnotic effects. We propose that DlgS97/SAP97 plays an important and conserved role in the development of tolerance to ethanol via NMDA receptor-mediated synaptic plasticity.
authors.affiliation: Ernest Gallo Clinic and Research Center, Emeryville, CA, USA.
authors.forename: Rajani
authors.initials: R
authors.lastname: Maiya
authors.forename: Seonok
authors.initials: S
authors.lastname: Lee
authors.forename: Karen H
authors.initials: KH
authors.lastname: Berger
authors.forename: Eric C
authors.initials: EC
authors.lastname: Kong
authors.forename: Justin B
authors.initials: JB
authors.lastname: Slawson
authors.forename: Leslie C
authors.initials: LC
authors.lastname: Griffith
authors.forename: Kogo
authors.initials: K
authors.lastname: Takamiya
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.forename: Ben
authors.initials: B
authors.lastname: Margolis
authors.forename: Ulrike
authors.initials: U
authors.lastname: Heberlein
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D000074288:Discs Large Homolog 1 Protein; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D051528:Guanylate Kinases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; C540765:Dnr1 protein, Drosophila; D029721:Drosophila Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C070350:dlg1 protein, Drosophila; D000431:Ethanol; D051528:Guanylate Kinases