Myles Akabas

Associate Professor
Physiology and Biophysics and of Neuroscience

Ullmann
Room 209
(718) 430-3360

Akabas Lab Web Site:
http://akabaslab.aecom.yu.edu/

Neurotransmitter-Gated Ion Channel Structure, Function and Dynamics

Neurotransmitter-gated ion channels are essential components in synaptic transmission. They transduce chemical signals into electrical signals. A long term goal of molecular neuroscience has been to provide an atomic level understanding of the structural bases for ligand specificity, signal transduction and channel properties in these receptors Our work focuses on the GABAA receptor and its relatives in the Cys-loop receptor gene superfamily that includes the glycine, nicotinic acetylcholine, and serotonin 5-HT3 receptors. The GABAA receptor is the target for drugs used clinically in the treatment of anxiety and epilepsy, and for general anesthesia. Acetylcholine receptors are targets for drugs of abuse, such as nicotine. Our goals are to understand the structural bases for the functional properties of these channels and to understand the molecular interactions by which drug binding modulates structure and channel activity. We use a combination of techniques including site-directed mutagenesis, heterologous expression, covalent chemical modification and electrophysiology. These studies have identified the residues lining the channel, the location of channel blocker binding sites and identified conformational changes occurring during channel gating and modulation by drugs, such as valium, propofol and alcohol.

 

Selected Publications

Horenstein, J., Wagner, D.A., Czajkowski, C. and Akabas, M.H. (2001) Protein mobility and GABA-induced conformational changes detected in the GABAA receptor channel-lining M2 segment. Nature Neuroscience 4:477-485.

Williams, D.B. and Akabas, M.H. (2002) Structural evidence that propofol stabilizes different GABAA receptor states at potentiating and activating concentrations. J. Neurosci. 22:7417-7424.

Bera, A.K., Chatav, M. and Akabas, M.H. (2002) GABAA receptor M2-M3 loop secondary structure and changes in accessibility during channel gating. J. Biol. Chem. 277:43002-43010.

Bali, M. and Akabas, M.H. (2004) Defining the propofol binding site location on the GABAA receptor. Mol. Pharmacol. 65:68-76.

Jung, S., Akabas, M.H. and Harris, R.A. (2005) Functional and structural analysis of the GABAA receptor (1 subunit during channel gating and alcohol modulation. J. Biol. Chem. 280:308-316.

Horenstein, J., Riegelhaupt, P. and Akabas, M.H. (2005) Differential protein mobility of the GABAA receptor and subunit channel-lining segments. J. Biol. Chem. 280:1573-1581.