Jonathan B. CohenDepartment of Neurobiology
Harvard Medical School
Warren Alpert Building, Room 314
220 Longwood Avenue, Boston, MA 02115
tel: (617) 432-1728; fax: (617) 734-7557
Our primary research interest is the analysis of the structure and function nicotinic acetylcholine receptors (AChR) and GABAa receptors. One research area concerns the structural basis of receptor gating. How does the structure of the AChR differ in different conformational states (closed channel, open channel, desensitized)? What determines whether a drug acts as an agonist (i.e., binds to the ACh site and causes the channel to open) or an antagonist? Why do many general anesthetics inhibit AChRs but facilitate activation of the structurally related GABAa receptor? To answer these questions, we use protein chemistry and biophysical techniques to map receptor structure, including drug binding sites, in different conformational states, and we use electrophysiological techniques to study the functional properties of mutant and chemically modified AChRs.
A second research area concerns the mechanisms that regulate the distribution of AChRs on the cell surface. At the neuromuscular junction AChRs are concentrated at very high density just under the nerve terminal, and that density decreases by orders of magnitude within several microns of the synapse. AChR “clustering” depends upon Rapsyn, a muscle protein that interacts with the cytoplasmic domain of the AChR and that serves as a scaffold protein linking AChRs to cytoskeletal proteins and also to other integral membrane proteins of the postsynaptic membrane, including tyrosine kinases that are receptors for nerve-derived factors that regulate AChR clustering.
Bianchetta, M.J., Betensky, R.A., and Cohen, J.B. (2005) Cell-surface MuSK self-association: a crucial role for the putative signal sequence. Biochemistry 44:16229-16238.
Arevalo, E., Chiara, D.C., Forman, S.A., Cohen, J.B., and Miller, K.W. (2005) Gating-enhanced accessibility of hydrophobic sites within the transmembrane region of the nicotinic receptor’s delta subunit: a time-resolved photolabeling study. J. Biol. Chem. 280:13631-13640.
Stewart, D.S., Chiara, D.C., and Cohen, J.B. (2006) Mapping the structural requirements for nicotinic acetylcholine receptor activation by use of tethered alkyltrimethylammonium agonists and antagonists. Biochemistry 45: 10641-10653.
Li, G.-D., Chiara, D.C., Sawyer, G.W., Husain, S.S., Olsen, R.W., and Cohen, J.B. (2006) Identification of a GABAa receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog. J. Neurosci. 26: 11599-11605.
Nirthanan, S., Garcia, G., Chiara, D.C., Husain, S.S., and Cohen, J.B. (2008) Identification of Binding Sites in the Nicotinic Acetylcholine Receptor for TDBzl-Etomidate, a Photoreactive Positive Allosteric Modulator. J. Biol. Chem. 283: 22051-22062.
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