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Neuregulin Signaling and GABAA Receptor Expression in Cerebellar Granule Neurons

Xie, Fang
http://rave.ohiolink.edu/etdc/view?acc_num=case1125415656

Abstract Details

2006, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
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 beta2 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 GABAA 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 GABAA 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 beta2 subunit expression in cerebellar granule neurons.
Ruth Siegel (Advisor)
165 p.
Neuregulin; ErbB receptors; GABAA receptor; Signaling; PSD-95; Egr-1; Cerebellum

Recommended Citations

Citations

  • Xie, F. (2006). Neuregulin Signaling and GABAA Receptor Expression in Cerebellar Granule Neurons [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1125415656

    APA Style (7th edition)

  • Xie, Fang. Neuregulin Signaling and GABAA Receptor Expression in Cerebellar Granule Neurons. 2006. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1125415656.

    MLA Style (8th edition)

  • Xie, Fang. "Neuregulin Signaling and GABAA Receptor Expression in Cerebellar Granule Neurons." Doctoral dissertation, Case Western Reserve University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1125415656

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.