Neuregulin induces GABAA receptor β2 subunit expression in cultured rat cerebellar granule neurons by activating multiple signaling pathways

The GABA(A) receptor beta subunit is required to confer sensitivity to gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS. In previous studies we demonstrated that the growth and differentiation factor neuregulin 1 (NRG1) selectively induced expression of the beta2 subunit mRNA and encoded protein in rat cerebellar granule neurons in culture. In the present report we examine the signaling pathways that mediate this effect. These studies demonstrate that the effects of NRG1 on beta2 subunit polypeptide expression require activation of the ErbB4 receptor tyrosine kinase; its effects are inhibited by pharmacological blockade of ErbB4 phosphorylation or reduction of receptor level with an antisense oligodeoxynucleotide. The NRG1-induced activation of ErbB4 stimulates the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and cyclin-dependent kinase-5 (cdk5) pathways. Pharmacological blockade of any of these pathways inhibits increased beta2 subunit expression, demonstrating that all three pathways are required to mediate the effects of NRG1 on GABA(A) receptor subunit expression in cerebellar granule neurons. These studies provide novel information concerning the actions of NRG1 on GABA(A) receptor expression in the CNS.