GABA regulates neural excitability and is known to be involved in a number of brain disorders including epilepsy. Therapeutic agents that modulate GABA receptors are currently used for sleep disorders, depression, mood disorders, and control of seizures, yet their mechanisms of action on the receptor are not well understood. As a basis for understanding these diseases and developing therapies, it is necessary to first elucidate the mechanism of GABA's interaction with its receptor. In order to do this, the GABA rho receptor, which forms a functional homomer, will be exogenously expressed in HEK cells and examined with electrophysiological methods. Chimera that switch portions of rho1 and rho2, as well as point mutations, will be constructed in order to determine the domains that are involved in receptor activation. Currents elicited by GABA will be measured and dose-response relationships of both wild-type and mutants will be determined. Regions that play a role in channel activation will be isolated by construction of progressively smaller chimera and point mutations. The single channel kinetics of wild type and select mutants will be studied to gain insight into the activation mechanism as well as the mechanism by which the mutations impair activation. The results from this project will lead to a better understanding of the structural domains and activation mechanism of the GABA receptor.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32MH011793-01A1
Application #
2637646
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Program Officer
Goldschmidts, Walter L
Project Start
1998-09-04
Project End
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Biology
Type
Schools of Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Wotring, V E; Miller, T S; Weiss, D S (2003) Mutations at the GABA receptor selectivity filter: a possible role for effective charges. J Physiol 548:527-40
Wotring, V E; Chang, Y; Weiss, D S (1999) Permeability and single channel conductance of human homomeric rho1 GABAC receptors. J Physiol 521 Pt 2:327-36