title: RhoGAP18B Isoforms Act on Distinct Rho-Family GTPases and Regulate Behavioral Responses to Alcohol via Cofilin.
abstract: Responses to the effects of ethanol are highly conserved across organisms, with reduced responses to the sedating effects of ethanol being predictive of increased risk for human alcohol dependence. Previously, we described that regulators of actin dynamics, such as the Rho-family GTPases Rac1, Rho1, and Cdc42, alter Drosophila's sensitivity to ethanol-induced sedation. The GTPase activating protein RhoGAP18B also affects sensitivity to ethanol. To better understand how different RhoGAP18B isoforms affect ethanol sedation, we examined them for their effects on cell shape, GTP-loading of Rho-family GTPase, activation of the actin-severing cofilin, and actin filamentation. Our results suggest that the RhoGAP18B-PA isoform acts on Cdc42, while PC and PD act via Rac1 and Rho1 to activate cofilin. In vivo, a loss-of-function mutation in the cofilin-encoding gene twinstar leads to reduced ethanol-sensitivity and acts in concert with RhoGAP18B. Different RhoGAP18B isoforms, therefore, act on distinct subsets of Rho-family GTPases to modulate cofilin activity, actin dynamics, and ethanol-induced behaviors.
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, United States of America; Program in Neuroscience, UT Southwestern Medical Center, Dallas, TX, United States of America.
authors.forename: Shamsideen A
authors.initials: SA
authors.lastname: Ojelade
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, United States of America.
authors.forename: Summer F
authors.initials: SF
authors.lastname: Acevedo
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, United States of America.
authors.forename: Geetha
authors.initials: G
authors.lastname: Kalahasti
authors.affiliation: Division of Nephrology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States of America.
authors.forename: Aylin R
authors.initials: AR
authors.lastname: Rodan
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, United States of America; Program in Neuroscience, UT Southwestern Medical Center, Dallas, TX, United States of America.
authors.forename: Adrian
authors.initials: A
authors.lastname: Rothenfluh
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000438:Alcohols / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002460:Cell Line; D048430:Cell Shape / Q000187:drug effects; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D023421:Models, Animal; D020033:Protein Isoforms / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D000438:Alcohols; C090145:Cdc42 protein, Drosophila; D029721:Drosophila Proteins; D020690:GTPase-Activating Proteins; D006993:Hypnotics and Sedatives; D020033:Protein Isoforms; C090146:Rac1 protein, Drosophila; C000607926:RhoGAP18B protein, Drosophila; D019204:GTP-Binding Proteins; C511153:Rho1 protein, Drosophila; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins