David Wagner
Assistant Professor

B.S. 1987, University of Illinois at Urbana-Champaign
Ph.D. 1997, University of Illinois at Chicago
Postdoctoral Fellow, University of Wisconsin-Madison

WLS 506
(414) 288-7366
email: david.wagner@marquette.edu

Structure, Function, and Modulation of GABAA Receptors

Our lab is interested in the biophysical properties of  GABAA receptors.  GABAA receptors, ligand-gated ion channels activated by the neurotransmitter g-aminobutyric acid (GABA), are present on the surface of virtually every neuron in the adult brain. Physiologically, GABAA receptors are responsible for the majority of fast inhibitory neurotransmission, a fundamental component of information processing in the brain that is important for synchronizing neural networks and mediating rhythmic activity associated with cognition.  In addition, the GABAA receptor is the target for a wide array of pharmacologically important agents.  These include: general anesthetics, anti-convulsants, barbiturates, benzodiazepines and ethanol.  Finally, GABAA mediated inhibition is implicated in disorders that include anxiety, epilepsy, and postpartum depression.

The primary goal of our research is to understand the biophysical processes that govern the interaction between GABA and the GABAA receptor and to determine how binding of a GABA molecule causes the receptor protein to change its shape so that an ion channel opens.  To this end we combine the methods of patch-clamp recording, ultra-fast solution exchange, kinetic analysis and molecular modeling.

Recent work in the lab has focused on the contribution to GABA binding by a series of arginines that are located in or near to the ligand binding pocket.  We have demonstrated that three of these residues are critical for maintaining the stability of the ligand-receptor complex. Since, arginine side chains are positively charged we believe it likely that one or more of these residues directly interacts with the negatively charged carboxyl group on the GABA molecule. 

Other ongoing projects in the lab include: The effects of ethanol on GABAA receptor kinetics, a survey of GABAA receptor stoichiometry using imaging techniques, and temperature dependence of GABAA kinetics.

Selected Publications

Wagner, D.A., Czajkowski, C., Jones, M.V., 2004. An arginine involved in GABA binding and unbinding but not in gating of the GABAA receptor. J. Neurosci. 24(11):2733-2741.

Kucken, A., Teissere, J., Seffinga-Clark, J., Wagner, D.A., and Czajkowski, C., 2003. Characterizing the interaction of imidazobenzodiazepines with the benzodiazepine binding site on GABAA receptors. Mol Pharm 62:1, 1-8.

Bowser, D. N.*, Wagner, D.A.* , Czajkowski, C., Cromer, B.A., Parker, M.W., Wallace, R.H., Harkin, L.A., Mulley, J.C., Marini, C., Berkovic, S.F., Williams, D.A., Jones, M.V., and Petrou S. 2002. Altered kinetics and benzodiazepine sensitivity of a GABAA receptor subunit mutation (g2R43Q) found in human epilepsy. PNAS 99:23, 15170-15175. (* D.N.B. and D.A.W contributed equally to this work)

Wagner D.A., Czajkowski C., 2001. Structure and dynamics of the GABA binding pocket: a narrowing cleft that constricts during activation. J. Neurosci.21:1, 67-74.

Horenstein, J., Wagner, D.A., Czajkowski, C., and Akabas, M., 2001. Protein mobility and GABA induced conformational changes in GABAA receptor pore-lining M2 segment. Nature Neurosci. 4:5, 477-485.