  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.
