title: Alcohol Regulates BK Surface Expression via Wnt/β-Catenin Signaling.
abstract: It has been suggested that drug tolerance represents a form of learning and memory, but this has not been experimentally established at the molecular level. We show that a component of alcohol molecular tolerance (channel internalization) from rat hippocampal neurons requires protein synthesis, in common with other forms of learning and memory. We identify β-catenin as a primary necessary protein. Alcohol increases β-catenin, and blocking accumulation of β-catenin blocks alcohol-induced internalization in these neurons. In transfected HEK293 cells, suppression of Wnt/β-catenin signaling blocks ethanol-induced internalization. Conversely, activation of Wnt/β-catenin reduces BK current density. A point mutation in a putative glycogen synthase kinase phosophorylation site within the S10 region of BK blocks internalization, suggesting that Wnt/β-catenin directly regulates alcohol-induced BK internalization via glycogen synthase kinase phosphorylation. These findings establish de novo protein synthesis and Wnt/β-catenin signaling as critical in mediating a persistent form of BK molecular alcohol tolerance establishing a commonality with other forms of long-term plasticity.
  
  
  
  Alcohol tolerance is a key step toward escalating alcohol consumption and subsequent dependence. Our research aims to make significant contributions toward novel, therapeutic approaches to prevent and treat alcohol misuse by understanding the molecular mechanisms of alcohol tolerance. In our current study, we identify the role of a key regulatory pathway in alcohol-induced persistent molecular changes within the hippocampus. The canonical Wnt/β-catenin pathway regulates BK channel surface expression in a protein synthesis-dependent manner reminiscent of other forms of long-term hippocampal neuronal adaptations. This unique insight opens the possibility of using clinically tested drugs, targeting the Wnt/β-catenin pathway, for the novel use of preventing and treating alcohol dependency.
authors.affiliation: Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico 00901, Steven.Treistman@upr.edu Cristina.Velazquez1@upr.edu.
authors.forename: Cristina
authors.identifier: 0000-0002-3784-9791
authors.initials: C
authors.lastname: Velázquez-Marrero
authors.affiliation: Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico 00901, University of Puerto Rico Río Piedras Campus, San Juan, Puerto Rico 00931.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Burgos
authors.affiliation: Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico 00901, University of Puerto Rico Natural Sciences Department, Carolina Campus, San Juan, Puerto Rico 00984, and.
authors.forename: José O
authors.identifier: 0000-0002-6349-0583
authors.initials: JO
authors.lastname: García
authors.affiliation: Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico 00901.
authors.forename: Stephanie
authors.identifier: 0000-0003-3706-5628
authors.initials: S
authors.lastname: Palacio
authors.affiliation: Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico 00901.
authors.forename: Héctor G
authors.identifier: 0000-0001-9387-5524
authors.initials: HG
authors.lastname: Marrero
authors.affiliation: Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico 00901.
authors.forename: Alexandra
authors.identifier: 0000-0001-7384-6187
authors.initials: A
authors.lastname: Bernardo
authors.affiliation: RCMI Translational Proteomics Center University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico 00936.
authors.forename: Juliana
authors.initials: J
authors.lastname: Pérez-Laspiur
authors.affiliation: Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico 00901, University of Puerto Rico Río Piedras Campus, San Juan, Puerto Rico 00931.
authors.forename: Marla
authors.initials: M
authors.lastname: Rivera-Oliver
authors.affiliation: Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico 00901.
authors.forename: Garrett
authors.identifier: 0000-0002-7159-5131
authors.initials: G
authors.lastname: Seale
authors.affiliation: Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico 00901, Steven.Treistman@upr.edu Cristina.Velazquez1@upr.edu.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Treistman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004361:Drug Tolerance; D000431:Ethanol / Q000494:pharmacology*; D038341:Glycogen Synthase Kinases / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000096:biosynthesis* / Q000187:drug effects; D009473:Neuronal Plasticity; D009474:Neurons / Q000187:drug effects; D010766:Phosphorylation; D017354:Point Mutation; D051381:Rats; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002492:Central Nervous System Depressants; D051036:Large-Conductance Calcium-Activated Potassium Channels; D051176:beta Catenin; D000431:Ethanol; D038341:Glycogen Synthase Kinases
keywords: BK; EtOH; Wnt; beta-catenin; downregulation; tolerance