TY - JOUR
T1 - RhoGAP18B isoforms act on distinct rho-family gtpases and regulate behavioral responses to alcohol via cofilin
AU - Ojelade, Shamsideen A.
AU - Acevedo, Summer F.
AU - Kalahasti, Geetha
AU - Rodan, Aylin R.
AU - Rothenfluh, Adrian
N1 - Publisher Copyright:
© 2015 Ojelade et al.
PY - 2015/9/14
Y1 - 2015/9/14
N2 - 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 ethanolinduced 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 Rho- GAP18B-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.
AB - 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 ethanolinduced 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 Rho- GAP18B-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.
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U2 - 10.1371/journal.pone.0137465
DO - 10.1371/journal.pone.0137465
M3 - Article
C2 - 26366560
AN - SCOPUS:84947753185
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 9
M1 - e0137465
ER -