Lisa M. Sharkey

 

 

E-mail: lmsharkey@wisc.edu

Research Project:

The research for my PhD thesis has focused on understanding the structure and function of the gamma-aminobutyric acid type A (GABA-A) receptor. The GABA-A receptor is a member of the ligand-gated ion channel (LGIC) family and mediates the majority of synaptic inhibition in the brain. The GABA-A receptor is responsible for transducing the effects of clinically important compounds such as volatile anesthetics, benzodiazepines (BZDs) and barbiturates. In order to understand how these drugs exert their effects and to facilitate new drug design, it is important to both characterize the molecular structure of the binding sites and to understand the cascade of structural changes in the protein that result in gating and pharmacological modulation of the ion channel.

My doctoral research has considered the question of how benzodiazepines modulate the GABA-A receptor in three ways:

• Allosteric Coupling of the GABA and BZD Binding Sites

• Identification of a Specific Protein Domain Responsible for GABA and BZD Site Linkage

• The Role of the y2 Subunit in GABA-A Receptor Gating and Benzodiazepine Modulation

Abstracts and Publications:

• Sharkey, L.M. and C. Czajkowski. Evidence that the two alpha1 subunit interfaces (alpha/gamma and alpha/beta) of the GABAA receptor are structurally different and play different roles in receptor function. Submitted.
• Sharkey, L.M. and C. Czajkowski. 2004. Asymmetric movements in the a1 and g2 subunits of the GABA-A receptor during channel gating. Gordon Conference on Ligand Recognition and Molecular Gating (Ventura, CA). In press.
• Sharkey, L.M. and C. Czajkowski. 2003. GABA but not pentobarbital mediates structural movements at the benzodiazepine binding site of the GABA-A receptor. Submitted.
• Boileau, A.J., R. Baur, L.M. Sharkey, E. Sigel and C. Czajkowski. 2002. The relative amount of cRNA coding for gamma2 subunits effects stimulation by benzodiazepines in GABAA receptors expressed in xenopus oocytes. Neuropharmacology. 43: 695-700. [PDF]
• Sharkey, L.M., and C. Czajkowski. 2002. Evidence that the two alpha1 unit interfaces (alpha/gamma and alpha/beta) of the GABAA receptor are structurally different and play different roles in receptor function. Soc. Neurosci. Abstr.
• Sharkey, L.M., H. Wang, E.V. Kuzhikandathil, and G.S. Oxford. 1999. Mutations in the putative sixth transmembrane domain provide evidence for multimerization of the VR1 receptor. Soc. Neurosci. Abstr.