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J. Biol. Chem. 277 (11): 9036-9042

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Activation Mechanism of Gi and Go by Reactive Oxygen Species*,

Motohiro NishidaDagger §, Kevin L. Schey, Shuichi TakagaharaDagger , Kenji Kontani||, Toshiaki Katada||, Yasuteru Urano**, Tetsuo Nagano**, Taku NagaoDagger , and Hitoshi KuroseDagger Dagger Dagger

From the Laboratory of Dagger  Pharmacology and Toxicology, || Physiological Chemistry, and ** Bioorganic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, § Division of Molecular and Cellular Physiology, Center for Integrative Bioscience, National Institute for Physiological Sciences, Myodaiji-cho, Okazaki 444-8585, Japan, and  Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29403

Reactive oxygen species are proposed to work as intracellular mediators. One of their target proteins is the alpha  subunit of heterotrimeric GTP-binding proteins (Galpha i and Galpha o), leading to activation. H2O2 is one of the reactive oxygen species and activates purified Galpha i2. However, the activation requires the presence of Fe2+, suggesting that H2O2 is converted to more reactive species such as ·OH. The analysis with mass spectrometry shows that seven cysteine residues (Cys66, Cys112, Cys140, Cys255, Cys287, Cys326, and Cys352) of Galpha i2 are modified by the treatment with ·OH. Among these cysteine residues, Cys66, Cys112, Cys140, Cys255, and Cys352 are not involved in ·OH-induced activation of Galpha i2. Although the modification of Cys287 but not Cys326 is required for subunit dissociation, the modification of both Cys287 and Cys326 is necessary for the activation of Galpha i2 as determined by pertussis toxin-catalyzed ADP-ribosylation, conformation-dependent change of trypsin digestion pattern or guanosine 5'-3-O-(thio)triphosphate binding. Wild type Galpha i2 but not Cys287- or Cys326-substituted mutants are activated by UV light, singlet oxygen, superoxide anion, and nitric oxide, indicating that these oxidative stresses activate Galpha i2 by the mechanism similar to ·OH-induced activation. Because Cys287 exists only in Gi family, this study explains the selective activation of Gi/Go by oxidative stresses.

* This research was supported in part by a grant from the Ministry of Education, Science, Sports, and Culture of Japan (to T. Nagao and H. Kurose). M. Nishida is a recipient of a grant from the Japan Society for the Promotion of Science for Young Scientists.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental table.

Dagger Dagger To whom correspondence should be addressed. Tel.: 81-3-5841-4863; Fax: 81-3-5841-4867; E-mail: kurose@mol.f.u-tokyo.ac.jp.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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