Tim G. Hales , PH.D.
Professor of Pharmacology and Physiology & Director of the Neuroscience Track in Molecular Medicine Ph.D. Program
Research Interests
Publications

POSITIONS AVAILABLE: http://www.gwumc.edu/pharm/positions.htm

RESEARCH INTERESTS
The primary focus of my lab is on the structural determinants of function in cys-loop receptors, neurotransmitter activated ion channels related to the nicotinic acetylcholine receptor (nAChR). Cys-loop receptors are found in neurons either in the postsynaptic membrane where they rapidly respond to the phasic release of neurotransmitters from synaptic vesicles (giving rise to excitatory or inhibitory postsynaptic potentials), or extrasynaptically where they can respond tonically to ambient levels of neurotransmitter (contributing to resting membrane potential). These receptors are targets for therapeutic agents that treat numerous ailments – from nausea to seizures. They are also the sites of action for several abused substances and mutations in genes encoding these receptors are associated with congenital neurological disorders (e.g. epilepsy and myasthenic syndrome).

We are studying the heterogeneity of cys-loop receptors. What are the structural requirements for each receptor's set of unique functional properties? How do drugs and mutatagenesis modify their properties? We use molecular and functional techniques to address these questions. Our primary functional techniques are patch-clamp electrophysiological recording and fluorescence imaging of intracellular Ca2+.

There are five classes of cys-loop receptor: the nAChR, 5-hydroxytryptamine activated (5-HT3) receptor, the zinc-activated ion channel (ZAC), gamma-aminobutyric acid-activated (GABAA) receptor and the glycine receptor. Each receptor is comprised of five subunits arranged in the form of a rosette around the central ion channel. Receptors are said to be either homomeric (five repeats of the same subunit) or heteromeric (contain two or more different types of subunit). There are many subtypes of (GABAA) and nAChR receptors. Their heterogeneity is caused by multiple genes encoding numerous different subunits and, to a lesser extent, by alternative splicing of transcripts encoding specific (GABAA) and nAChR subunits.

We are developing a web resource devoted to structure-function analysis of cys-loop receptors: http://www.gwumc.edu/pharm/cys-loop.htm

SELECTED PUBLICATIONS

Davies, P.A., Hanna, M.C., Hales, T.G ., and Kirkness, E.F. Insensitivity to anaesthetic agents conferred by a class of GABA A receptor subunit. Nature . 385: 820-823 (1997).

Bronstein, J.M., Hales, T.G ., Tyndale, R.F. and Charles, A.C. A conditionally immortalized glial cell line that expresses mature myelin proteins and functional GABA A receptors. J. Neurochem . 70: 483-490 (1998).

Davies, P.A., Pistis, M., Hanna, M.C., Peters, J.A., Lambert, J.J., Hales, T.G ., and Kirkness, E.F. The 5-HT 3B subunit is a major determinant of serotonin receptor function. Nature . 397: 359-363 (1999).

Charles, A.C., Piros, E.T., Evans, C.J. and Hales, T.G . L-type Ca 2+ channels and K + channels specifically modulate the frequency and amplitude of spontaneous Ca 2+ oscillations and have distinct roles in prolactin release in GH 3 cells. J. Biol. Chem . 274: 7508-7515 (1999).

Davies, P.A., Hoffmann, E.B., Carlisle, H.J., Tyndale, R.F. and Hales, T.G. The influence of an endogenous b 3 subunit on recombinant GABA A receptor assembly and pharmacology in WSS-1 cells and transiently transfected HEK293 cells. Neuropharmacol. 39: 611-620 (2000).

Hanna, M.C., Davies, P.A., Hales, T.G . and Kirkness, E.F. Evidence for expression of heteromeric serotonin 5-HT 3 receptors in rodents. J. Neurochem . (2000), 75: 240-247.

Prather, P.L., Song, L., Piros, E.T., Law, P.Y., and Hales, T.G . d- Opioid receptors are more efficiently coupled to adenylyl cyclase than to L-type Ca 2+ channels in transfected rat pituitary cells. J. Pharmacol. & Exp. Therapeutics . (2000), 295: 552-562.

Davies, P.A., Kirkness, E.F. and Hales, T.G. Evidence for the formation of functionally distinct abge GABAA receptors. J. Physiol . (2001), 537.1: 101-113.

Safa, P., Boulter, J. and Hales, T.G. Functional properties of Ca V 1.3 ( a 1D ) L-type Ca 2+ channel splice variants expressed by rat brain and neuroendocrine GH 3 cells. J. Biol. Chem . (2001), 276: 38727-38737.

Irnaten, M., Walwyn, W.M., Wang, J., Venkatesan, P., Evans, C., B.A., Chang, K.S.K., Andresen, M.C., Hales, T.G ., and Mendelowitz, D. Pentobarbital enhances GABAergic neurotransmission to cardiac parasympathetic neurons which is prevented by expression of GABA A e subunit. Anesthesiology . (2002), 97: 717-724.

Davies, P.A., McCartney, M.R., Wang, W., Hales, T.G ., and Kirkness, E.F. Alternative transcripts of the GABA A receptor e subunit in human and rat. Neuropharmacol . (2002), 43:467-475.

Davies, P.A., Wang, W., Hales, T.G ., and Kirkness, E.F. Novel class of ligand-gated ion channel is activated by Zn 2+ . J. Biol. Chem. (2003), 278:712-717.

Charles, A.C., Mostovskaya, N., Asas, K., Evans, C.J., Dankovitch, M.L., and Hales, T.G . Co-expression of d opioid receptors with d receptors in GH 3 cells changes the functional response to m agonists from inhibitory to excitatory. Mol. Pharmacol . (2003), 63:89-95.

Stewart, A., Davies, P.A., Kirkness, E.F., Safa, P., and Hales, T.G . Introduction of the 5-HT 3B subunit alters the functional properties of 5-HT 3 receptors native to neuroblastoma cells. Neuropharmacol. (2003), 44:212-221.

Hales, T.G ., Tang, H., Bollan, K., Johnson, S., King, D., and Connolly, C.N. The epilepsy mutation, gamma2(R43Q) disrupts a highly conserved inter-subunit contact site, perturbing the biogenesis of GABA A receptors. Mol Cell Neurosci . (2005) 29:120-7

Walwyn, W., Maidment, N.T., Sanders, M., Evans, C.J., Kieffer, B.L., Hales, TG . Induction of d opioid receptor function by up-regulation of membrane receptors in mouse primary afferent neurons. Mol. Pharmacol . (2005) 68: 1688-1698.

Wagner, D.A., Goldschen-Ohm, M.P., Hales, T.G. , Jones, M.V. Kinetics and spontaneous open probability conferred by the epsilon subunit of the GABA A receptor. J Neurosci . (2005) 25: 10462-10468.

Hales, T.G. , Dunlop, J.I., Deeb, T.Z., Carland, J.E., Kelley, S.P., Lambert, J.J., Peters, J.A. Common determinants of single channel conductance within the large cytoplasmic loop of 5-hydroxytryptamine type 3 and a4b2 nicotinic acetylcholine receptors. J. Biol. Chem . (2006) 281: 8062-8071.

Hales, T.G. , Deeb, T.Z., Tang, H., Bollan, K.A., King, D.P., Johnson, S.J., Connolly, C.N. An asymmetric contribution to GABA A receptor function of a conserved lysine within TM2-3 of a 1, b 2 and g 2 subunits. J. Biol Chem. (2006), 281:17034-43.

Deeb, T.Z., Carland, J.E., Cooper, M.A., Livesey, M.R., Lambert, J.J., Peters, J.A., Hales, T.G. Dynamic modification of a mutant cytoplasmic cysteine residue modulates the conductance of the human 5-HT 3A receptor. J Biol Chem. (2007) 282:6172-82.

McCartney, M.R., Deeb, T.Z., Henderson , T.N., Hales, T.G . Tonically active GABA A receptors in hippocampal pyramidal neurons exhibit constitutive GABA-independent gating. Mol Pharmacol. (2007) 71(2):539-48.

Walwyn W., Evans C.J., Hales T.G. b -Arrestin2 and c-Src regulate the constitutive activity and recycling of m opioid receptors in dorsal root ganglion neurons. J Neurosci. (2007) 27(19):5092-104.

Last updated: 5/22/07