Myles Akabas

Associate Professor
Molecular biophysics of neurotransmitter-gated ion channels. GABA-A receptors, general anesthetics, ion channel structure, function and pharmacology.

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. Molecular neuroscience has sought 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

Bali, M., Jansen, M., and Akabas, M.H. (2009) GABA-induced intersubunit conformation movement in the GABAA receptor α1M1-β2M3 transmembrane subunit interface: Experimental basis for homology modeling of an intravenous anesthetic binding site. J. Neurosci. (in press).

Jansen, M., Bali, M. and Akabas, M.H. (2008) Modular design of Cys-loop ligand-gated Ion channels: Functional 5-HT3 and GABA ρ1 receptors lacking the large cytoplasmic M3M4 loop. J Gen Physiol. 131:137-46.

Rosen, A., Bali, M., Horenstein, J. and Akabas, M.H. (2007) Channel opening by general anesthetics and GABA induce similar conformational changes in the GABAA receptor M2 channel-lining segment. Biophy. J. 92:3130-3139.

Bali, M. and Akabas, M.H. (2007) The location of a closed channel gate in GABAA receptor channels. J. Gen. Physiol. 129:145-159.

Jansen, M. and Akabas, M.H. (2006) State-dependent cross-linking of M2 and M3: Functional basis for the alignment of GABAA and ACh receptor M3 segments. J. Neurosci. 26:4492-4499.