David S. Weiss, Ph.D.

Professor and Dean of the Graduate School of Biomedical Sciences

Education

B.A., University of North Carolina at Chapel Hill, 1980
Ph.D., Baylor College of Medicine, 1987

Research

y-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. Dysfunctions of GABA-mediated inhibition have been implicated in the etiology of a variety of brain disorders such as epilepsy. Furthermore, GABA receptors are a target for a variety of therapeutic, neuroactive compounds such as benzodiazepines and barbiturates.

GABA, released at presynaptic terminals, diffuses across the synaptic cleft and binds to the pentameric GABA receptors on the postsynaptic membrane. First and foremost, what is the mechanism by which the binding of agonist (GABA) leads to the opening of the chloride-selective pore? Also, once open, how does the pore allow 106 chloride ions per second to flow across the membrane, but essentially no cations? A third question addresses the mechanism by which allosteric compounds such as benzodiazepines (diazepam) and barbiturates (pentobarbital) alter channel function. How does the GABAergic neuron regulate the number of postsynaptic GABA receptors on the cell surface. To address these questions we use a variety of molecular biological, biochemical, pharmacological, electrophysiological, and biophysical techniques to gain insight into the structure and function of GABA receptor activation, permeation, modulation, and regulation.

Publications

Khatri A, Weiss DS. The role of Loop F in the activation of the GABA receptor. J Physiol. 2010 Jan 1;588(Pt 1):59-66.

Li P, Khatri A, Bracamontes J, Weiss DS, Steinbach JH, Akk G. Site-specific fluorescence reveals distinct structural changes induced in the human rho 1 GABA receptor by inhibitory neurosteroids. Mol Pharmacol. 2010 Apr;77(4):539-46.

Khatri A, Sedelnikova A, Weiss DS. Sructural Rearrangements in Loop F of the GABA Receptor Signal LIgand Binding, Not Channel Activation. Biophys J. 2009 Jan:96(1):45-55.

Zheleznova NN, Sedelnikova A, Weiss DS. Function and modulation of delta-containing GABA(A) receptors.Psychoneuroendocrinology. 2009 Sep 17.

Wotring VE, Weiss, DS. Charge scan reveals an extended region at the intracellular end of the GABA receptor pore that can influence ion selectivity.J Gen Physiol. 2008 Jan;131(1):87-97.

Erkkila, BE., Sedelnikova, AV, Weiss, DS. Stoichiometric pore mutations of the GABAAR reveal a pattern of hydrogen bonding with picrotoxin. Biophys J. 2008 Feb 29.

Zheleznova N, Sedelnikova A, Weiss, DS. alpha(1)beta(2)delta, a silent GABA(A) receptor: recruitment by tracazolate and neurosteroids.Br J Pharmacol. 2008 Mar;153(5):1062-71.

Campo-Soria C, Chang Y, Weiss DS. Mechanism of action of benzodiazepines on GABAA receptors. Br J Pharmacol. 2006 Aug;148(7):984-90.

Sedelnikova A, Erkkila BE, Harris H, Zakharkin SO, Weiss DS. Stoichiometry of a pore mutation that abolishes picrotoxin-mediated antagonism of the GABAA receptor.J Physiol. 2006 Dec 1;577(Pt 2):569-77.

Sedelnikova A, Smith CD, Zakharkin SO, Davis D, Weiss DS, Chang Y. Mapping the rho1 GABA(C) receptor agonist binding pocket. Constructing a complete model. J Biol Chem. 2005 Jan 14;280(2):1535-42.

Filippova N, Wotring VE, Weiss DS. Evidence that the TM1-TM2 Loop Contributes to the ρ1 GABA Receptor Pore. J Biol Chem. 2004 May 14;279(20):20906-14.

Wotring, V.E., Miller, T.S., and Weiss, D.S. Mutations at the GABA receptor selectivity filter: a possible role for effective charges. Journal of Physiology 548:527-540, 2003.

Weiss, D.S., and Chang, Y. Crystallizing our understanding of partial agonists. Nature Neuroscience. 2003 Aug;6(8):788-9, Aug 2003.

Chang, Y.C., Ghansah, E., Chen, Y., Ye, J., Weiss, D.S. Desensitization mechanism of GABA receptors revealed by single oocyte binding and receptor function. Journal of Neuroscience. 22, 7982-7990, 2002.

Chang, Y. and Weiss, D.S.. Site-specific fluorescence reveals distinct structural changes with GABA receptor activation and antagonism. . Nature Neuroscience. 5, 1163-1168, 2002.

Chang, Y. and Weiss, D.S. Channel opening locks agonist onto the GABAC receptor. Nature Neuroscience.2(3) 219-225, 1999.

Filippova, N., Dudley, R. and ,Weiss, D.S. Evidence for phosphorylation-dependent internalization of recombinant human GABAC receptors. Journal of Physiology. 518.2, 385-399, 1999.

Chang, Y., Wang, R., Barot, S. And Weiss, D.S., Stoichiometry of a recombinant GABA receptor, Journal of Neuroscience. 16:5415-5424, 1996.

Amin, J. And Weiss, D. S. Insights into the activation mechanism of rho1 GABA receptors obtained by coexpression of wild type and activation-impaired subunits. Proceedings of the Royal Society of London.263:272-282, 1996.

Amin, J. and Weiss, D. S. GABAA receptor needs two homologous domains of the ß subunit for activation by GABA, but not by pentobarbital. Nature. 366: 565-569, 1993.