Neurobiology

Jonathan B. Cohen, Ph.D.

Professor of Neurobiology

Cohen Lab Website: http://www.hms.harvard.edu/bss/neuro/cohen/

Our research focuses on the fundamental mechanisms involved in information transfer between nerve cells or between nerve and muscle. We study the contacts between cells (synapses) where acetylcholine is the chemical signal released from the input neuron and nicotinic acetylcholine receptors (AChRs) are the cell surface receptors that bind acetylcholine. The AChRs are complex proteins made up of five subunits that together contain both the binding site for acetylcholine and the structure of an ion channel that is opened when acetylcholine (ACh) binds, resulting in a change of electrical potential in the target cell within a fraction of a millisecond. These receptors mediate neural control of the contraction of all skeletal muscles, and as such they are the target of action of the muscle relaxants used by anesthesiologists and the AChR is the protein that is destroyed in an autoimmune disease, myasthenia gravis. These receptors are also distributed widely throughout the brain where they are the site of binding of nicotine and the potential target of novel drugs that could reproduce many of the cognitive and performance-enhancing effects of nicotine without the undesirable actions.

One research area concerns the mechanism of permeability control by the AChR. What portions of the receptor contribute to the ACh binding site or to the structure of the ion channel? How does the binding of ACh change the structure of the AChR? What determines whether a drug acts as an agonist (i.e. bind to the ACh site and open the channel ) or an inhibitor? When drugs block the action of ACh without preventing its binding, where do they bind in the AChR? To answer these questions, protein chemistry and immunological techniques are being used to characterize the structure of the AChR, and electrophysiological techniques are being used to analyze functional properties of mutant and chemically modified AChRs.

A second research area concerns the mechanisms involved in the precise positioning of AChRs in the muscle cell surface just underlying the nerve terminal (the post-synaptic membrane). A striking feature of the nerve-muscle synapse and also of synapses in the brain involving ligand-gated ion channels is the fact that receptors are concentrated at very high density just under the nerve terminal, and that density is 100-500 fold lower on the rest of the cell surface. 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. Experiments are underway to characterize how Rapsyn organizes the highly specialized structure of the nicotinic postsynaptic membrane.