Mechanisms of insulin action on GABA-A receptors.
Published: 2004
Language: eng
Number of pages: 138
Description: Insulin is an important neuromodulator that plays multiple roles within the brain. One such effect of insulin, is to enhance inhibitory GABA-ergic synaptic transmission, by increasing the number of GABAA receptors on the surface of neurons. This thesis examines the molecular mechanisms underlying insulin-induced changes in GABAA receptor function, including cell surface expression of the receptor. As PI3-kinase (PI3-K) is a key mediator of the insulin response, and because it plays a well-known role in protein trafficking, we have chosen to focus our studies on this enzyme. We have found that PI3-K, which is activated in the brain following insulin treatment, plays a role in the insulin-stimulated potentiation of GABA A receptor-mediated currents. Additionally, PI3-K is necessary for the increase in GABAA receptor numbers at the plasma membrane after insulin stimulation. Tyrosine residues within the beta2 subunit of the GABA A receptor may mediate this effect. We have also shown that the interaction between PI3-K and the GABAA receptor is enhanced in response to insulin, and that this association is dependent on tyrosine phosphorylation. The N-terminal SH2 domain of the p85 regulatory subunit of PI3-K appears to mediate this association. The activation of GABAA receptor-associated PI3-K is increased following insulin treatment. The beta2 subunit of the GABAA receptor may be important for this increase. Taken together, our results suggest a mechanism whereby insulin can regulate changes in synaptic transmission through its downstream actions on the GABAA receptor.
Notes: Adviser:  Yu Tian Wang.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 5020.
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