Dominant role of GABAB2 and Gbetagamma for GABAB receptor-mediated-ERK1/2/CREB pathway in cerebellar neurons

摘要

gamma-aminobutyric acid type B (GABA(B)) receptor is an allosteric complexmade of two subunits, GABA(B1) and GABA(B2). GABA(B2) plays a major role in thecoupling to G protein whereas GABA(B1) binds GABA. It has been shown thatGABA(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 theselective agonist baclofen induces ERK(1/2) phosphorylation in culturedcerebellar granule neurons. We also show that CGP7930, a positive allostericregulator specific of GABA(B2), alone can induce the phosphorylation ofERK(1/2). PTX, a G(i/o) inhibitor, abolishes both baclofen andCGP7930-mediated-ERK(1/2) phosphorylation. Moreover, both baclofen and CGP7930induce ERK-dependent CREB phosphorylation. Furthermore, by using LY294002, aPI-3 kinase inhibitor, and a C-term of GRK-2 that has been reported tosequester Gbetagamma subunits, we demonstrate the role of Gbetagamma in GABA(B)receptor-mediated-ERK(1/2) phosphorylation. In conclusion, the activation ofGABA(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 theactivation of CREB. These findings suggest a role of GABA(B) receptor inlong-term change in the central nervous system.