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

TL;DR

This study uncovers that GABA(B) receptor activation in cerebellar neurons triggers ERK1/2 and CREB phosphorylation mainly through GABA(B2) coupling to G(i/o) proteins and Gbetagamma subunits, indicating a role in neural plasticity.

Contribution

It reveals the specific molecular mechanisms by which GABA(B) receptor activates ERK1/2 and CREB, emphasizing the dominant role of GABA(B2) and Gbetagamma in cerebellar neurons.

Findings

GABA(B) activation induces ERK1/2 phosphorylation in cerebellar neurons.

GABA(B2) and Gbetagamma are crucial for ERK pathway activation.

GABA(B) receptor influences long-term neural changes.

Abstract

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.