Dominant role of GABAB2 and Gbetagamma for GABAB receptor-mediated-ERK1/2/CREB pathway in cerebellar neurons.
gamma-aminobutyric acid type B (GABA(B)) receptor is an allosteric complex made of two subunits, GABA(B1) and GABA(B2). GABA(B2) plays a major role in the coupling to G protein whereas GABA(B1) binds GABA. It has been shown that GABA(B) receptor activates ERK(1/2) in neurons of the central nervous system, but the molecular mechanisms underlying this event are poorly characterized. Here, we demonstrate that activation of GABA(B) receptor by either GABA or the selective agonist baclofen induces ERK(1/2) phosphorylation in cultured cerebellar granule neurons. We also show that CGP7930, a positive allosteric regulator specific of GABA(B2), alone can induce the phosphorylation of ERK(1/2). PTX, a G(i/o) inhibitor, abolishes both baclofen and CGP7930-mediated-ERK(1/2) phosphorylation. Moreover, both baclofen and CGP7930 induce ERK-dependent CREB phosphorylation. Furthermore, by using LY294002, a PI-3 kinase inhibitor, and a C-term of GRK-2 that has been reported to sequester Gbetagamma subunits, we demonstrate the role of Gbetagamma in GABA(B) receptor-mediated-ERK(1/2) phosphorylation. In conclusion, the activation of GABA(B) receptor leads to ERK(1/2) phosphorylation via the coupling of GABA(B2) to G(i/o) and by releasing Gbetagamma subunits which in turn induce the activation of CREB. These findings suggest a role of GABA(B) receptor in long-term change in the central nervous system.
Tu
Haijun
H
Sino-France Laboratory for Drug Screening, Key Laboratory of Molecular Biophysics, Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Rondard
Philippe
P
Xu
Chanjuan
C
Bertaso
Federica
F
Cao
Fangli
F
Zhang
Xueying
X
Pin
Jean-Philippe
JP
Liu
Jianfeng
J
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002460:Cell Line; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D017362:Cyclic AMP Response Element-Binding Protein; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D021122:Protein Subunits; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D001418:Baclofen