TY - JOUR
T1 - Rsu1 regulates ethanol consumption in Drosophila and humans
AU - Ojelade, Shamsideen A.
AU - Jia, Tianye
AU - Rodan, Aylin R.
AU - Chenyang, Tao
AU - Kadrmas, Julie L.
AU - Cattrell, Anna
AU - Ruggeri, Barbara
AU - Charoen, Pimphen
AU - Lemaitre, Hervé
AU - Banaschewski, Tobias
AU - Büchel, Christian
AU - Bokde, Arun L W
AU - Carvalho, Fabiana
AU - Conrod, Patricia J.
AU - Flor, Herta
AU - Frouin, Vincent
AU - Gallinat, Jürgen
AU - Garavan, Hugh
AU - Gowland, Penny A.
AU - Heinz, Andreas
AU - Ittermann, Bernd
AU - Lathrop, Mark
AU - Lubbe, Steven
AU - Martinot, Jean Luc
AU - Pausu, Tomás
AU - Smolka, Michael N.
AU - Spanagel, Rainer
AU - O'Reilly, Paul F.
AU - Laitinen, Jaana
AU - Veijola, Juha M.
AU - Feng, Jianfeng
AU - Desrivières, Sylvane
AU - Jarvelin, Marjo Riitta
AU - Schumann, Gunter
AU - Rothenfluh, Adrian
PY - 2015/7/28
Y1 - 2015/7/28
N2 - Alcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts downstream of the integrin cell adhesion molecule and upstream of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase to regulate the actin cytoskeleton. In an ethanol preference assay, global loss of Rsu1 causes high naïve preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal naïve preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons tomodulate naïve and acquired ethanol preference. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating rewardrelated phenotypes, including ethanol consumption, across phyla.
AB - Alcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts downstream of the integrin cell adhesion molecule and upstream of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase to regulate the actin cytoskeleton. In an ethanol preference assay, global loss of Rsu1 causes high naïve preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal naïve preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons tomodulate naïve and acquired ethanol preference. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating rewardrelated phenotypes, including ethanol consumption, across phyla.
KW - Actin
KW - Addiction
KW - Alcohol
KW - Genetics
UR - http://www.scopus.com/inward/record.url?scp=84938150145&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84938150145&partnerID=8YFLogxK
U2 - 10.1073/pnas.1417222112
DO - 10.1073/pnas.1417222112
M3 - Article
C2 - 26170296
AN - SCOPUS:84938150145
SN - 0027-8424
VL - 112
SP - E4085-E4093
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 30
ER -