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J. Biol. Chem., Vol. 279, Issue 51, 53196-53204, December 17, 2004

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G₁₆-mediated Activation of Nuclear Factor B by the Adenosine A₁ Receptor Involves c-Src, Protein Kinase C, and ERK Signaling^*

Andrew M. F. Liu and Yung H. Wong

From the Department of Biochemistry, Molecular Neuroscience Center, and Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

The G_i-linked adenosine A1 receptor has been shown to mediate anti-inflammatory actions, possibly via modulation of the transcription factor nuclear factor-B (NFB). Here we demonstrate that an adenosine A1 agonist, N⁶-cyclohexyladenosine (CHA), activated IKK/ phosphorylation through PTX-insensitive G proteins in human lymphoblastoma Reh cells. To delineate the mechanism of action, different PTX-insensitive G proteins were expressed in human embryonic kidney 293 cells. Only G₁₆ supported the CHA-induced IKK phosphorylation and NFB-driven luciferase activity in time-dependent, dose-dependent, and PTX-insensitive manners. G subunits also modulated IKK/NFB, as indicated by the stimulatory actions of G₁₂ and the abrogation of CHA-induced response by transducin. The participation of phospholipase C, protein kinase C, and calmodulin-dependent kinase II in CHA-induced IKK/NFB activation were demonstrated by employing specific inhibitors and dominant-negative mutants. Inhibition of c-Src and numerous intermediates along the extracellular signal-regulated (ERK) kinase cascade including Ras, Raf-1 kinase, and MEK1/2 abolished the CHA-induced IKK/NFB activation. Although c-Jun N-terminal kinase and p38 MAPK were also activated by CHA, they were not required for the IKK/NFB regulation. Similar results were obtained using Reh cells. These data suggest that the G₁₆-mediated activation of IKK/NFB by CHA required a complex signaling network composed of multiple intermediates.

Received for publication, September 7, 2004 , and in revised form, October 8, 2004.

^* This work was supported in part by Grants from the Research Grants Council of Hong Kong (HKUST 6095/01M, 2/99C, and 3/03C), the University Grants Committee (AoE/B-15/01), and the Hong Kong Jockey Club. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of the Croucher Senior Research Fellowship. To whom correspondence should be addressed: Dept. of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Tel.: 852-2358-7328; Fax: 852-2358-1552; E-mail: boyung{at}ust.hk.

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