GABAA receptors convey the majority of synaptic inhibition in the CMS, the process by which excitation of a presynaptic interneuron prevents the excitation of a postsynaptic principal neuron. GABAA receptors also are important therapeutic targets for benzodiazepines and general anesthetics. Receptor function is also modulated by neurosteroids and many abused hypnotic drugs. Mutations in GABAA receptor genes have been linked to familial epilepsies, schizophrenia and autism. However, it is not known how these chemicals modulate receptor function or how these mutations contribute to receptor dysfunction or disease pathology at the molecular level. The receptor functions as a chemical to voltage transducer, converting inhibitory chemical signals into hyperpolarizing membrane potentials in a wide variety of neuronal cell types throughout the nervous system. When the amplitude, duration or timing of these inhibitory signals is altered either by drug or disease, the function of the CMS is profoundly altered. The underlying hypothesis of this work is that specific amino acids in the GABAA receptor b subunit define a novel allosteric coupling pathway in the GABAA receptor. The goals of this project are i) to characterize a new binding site on the receptor and ii) to better understand the molecular events that underpin the activation and modulation of fast inhibitory neurotransmission. Using the modern molecular pharmacologic tools of patch-clamp electrophysiology, site directed mutagenesis, kinetic and structure homology modeling, we have novel positions in the b subunit that are critical for the allosteric activation of the protein that precedes channel opening and for the modulation of channel activity by neuroactive chemicals. The results generated in these studies will represent a large step forward in understanding drug action on ligand-gated channels. Furthermore, these results may aid in understanding how inherited mutations in GABAA receptor genes contribute to the pathogenesis of diseases such as schizophrenia, autism and epilepsy. Finally, it is hoped that the characterization of the new modulatory binding site will provide us with a new target for treating neuropsychiatric diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM073959-05
Application #
7817127
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Cole, Alison E
Project Start
2006-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$226,499
Indirect Cost
Name
Emory University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Garton, Thomas P; He, Yangdong; Garton, Hugh J L et al. (2016) Hemoglobin-induced neuronal degeneration in the hippocampus after neonatal intraventricular hemorrhage. Brain Res 1635:86-94
Nash, Rodney; Krishnamoorthy, Malini; Jenkins, Andrew et al. (2012) Human embryonic stem cell model of ethanol-mediated early developmental toxicity. Exp Neurol 234:127-35
Rye, David B; Bliwise, Donald L; Parker, Kathy et al. (2012) Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors. Sci Transl Med 4:161ra151
O'Toole, Kate K; Jenkins, Andrew (2011) Discrete M3-M4 intracellular loop subdomains control specific aspects of γ-aminobutyric acid type A receptor function. J Biol Chem 286:37990-9
O'Shea, Sean M; Williams, Carrie A; Jenkins, Andrew (2009) Inverse effects on gating and modulation caused by a mutation in the M2-M3 Linker of the GABA(A) receptor gamma subunit. Mol Pharmacol 76:641-51
Trudell, James R; Yue, Minerva E; Bertaccini, Edward J et al. (2008) Molecular modeling and mutagenesis reveals a tetradentate binding site for Zn2+ in GABA(A) alphabeta receptors and provides a structural basis for the modulating effect of the gamma subunit. J Chem Inf Model 48:344-9
Jenkins, Andrew; Lobo, Ingrid A; Gong, Diane et al. (2008) General anesthetics have additive actions on three ligand gated ion channels. Anesth Analg 107:486-93
Richardson, James E; Garcia, Paul S; O'Toole, Kate K et al. (2007) A conserved tyrosine in the beta2 subunit M4 segment is a determinant of gamma-aminobutyric acid type A receptor sensitivity to propofol. Anesthesiology 107:412-8