Neuregulin signaling and GABA(A) receptor expression in cerebellar granule neurons.

摘要

The gamma-aminobutyric acid receptor A (GABAA-R) mediates the effects of GABA, the major inhibitory neurotransmitter in the CNS. The beta subunit of this receptor is required to confer sensitivity to GABA and thus is important for GABAA-R function. However, little is known about the regulation of this subunit in CNS.; Recent studies demonstrated that neuregulin-1 (NRG), a growth and differentiation factor, selectively induces the expression of the GABAA-R beta subunit in cerebellar granule neurons. The goal of my studies has been to identify the signaling and regulatory mechanism of NRG's effects on beta subunit expression in cerebellar granule neurons in culture. These studies have focused on the effect of NRG at the plasma membrane, its intracellular actions, and its effects in the nucleus.; Our findings demonstrate that the effects of NRG on beta2 subunit polypeptide expression require activation of the ErbB4 receptor tyrosine kinase. The NRG-induced activation of ErbB4 stimulates the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3-K) and cyclin-dependent kinase-5 (cdk5) pathways. All three pathways are required to mediate the effects of NRG on GABAA receptor subunit expression in cerebellar granule neurons.; Our results show that postsynaptic density protein 95 (PSD-95), a scaffolding protein, facilitates NRG-induced GABAA receptor beta2 subunit expression through its association with ErbB4. In addition, cdk5 activation enhances PSD-95 phosphorylation, which promotes ErbB4-PSD-95 interaction. These studies demonstrate that NRG's effect on GABAA receptor beta 2 subunit are enhanced by recruiting the participation of proteins involved in regulating synaptic plasticity.; Finally, initial studies have identified transcription factors that are downstream of the NRG-activated signaling cascades that are involved in GABA A receptor beta2 subunit expression. We found that early growth response 1 (Egr-1) is rapidly induced by NRG and lies downstream of NRG-activated MAPK and cdk5 pathways. Moreover, blockade of Egr-1 level attenuated NRG-induced GABAA receptor beta2 subunit expression. These findings suggest that Egr-1 is at least partially responsible for GABA A receptor beta2 subunit induction by NRG.; The three parts of the thesis research provide new knowledge about the molecular mechanism of NRG signaling in GABAA receptor beta 2 subunit expression in cerebellar granule neurons.