GABAB receptor-mediated ERK1/2 phosphorylation via a direct interaction with CaV1.3 channels

Abstract

Neuronal L-type Ca2+ channels play pivotal roles in regulating gene expression, cell survival, and synaptic plasticity. The CaV1.2 and CaV1.3 channels are 2 main subtypes of neuronal L-type Ca2+ channels. However, the specific roles of CaV1.2 and CaV1.3 in L-type Ca2+ channel-mediated neuronal responses and their cellular mechanisms are poorly elucidated. On the basis of our previous study demonstrating a physical interaction between the CaV1.3 channel and GABAB receptor (GABABR), we further examined the involvement of CaV1.2 and CaV1.3 in the GABABR-mediated activation of ERK1/2, a kinase involved in both CREB activation and synaptic plasticity. After confirming the involvement of L-type Ca2+ channels in baclofen-induced ERK1/2 phosphorylation, we examined a specific role of CaV1.2 and CaV1.3 channels in the baclofen effect. Using siRNA-mediated silencing of CaV1.2 or CaV1.3 messenger, we determined the relevance of each channel subtype to baclofen-induced ERK1/2 phosphorylation in a mouse hippocampal cell line (HT-22) and primary cultured rat neurons. In the detailed characterization of each subtype using HEK293 cells transfected with CaV1.2 or CaV1.3, we found that GABABR can increase ERK1/2 phosphorylation and CaV1.3 channel activity through direct interaction with CaV1.3 channels. These results suggest a functional interaction between CaV1.3 and GABABR and important implications of CaV1.3/GABABR clusters for translating synaptic activity into gene expression alterations.