Jonathan B. Cohen
Department of Neurobiology, Harvard Medical School
Research in the Cohen lab focuses on molecular studies of receptors for GABA, the major inhibitory neurotransmitter in the brain, and acetylcholine, an excitatory neurotransmitter in many brain regions and at nerve-muscle contacts.
Our current research focuses on molecular studies of receptors for GABA, the major inhibitory neurotransmitter in the brain, and acetylcholine, an excitatory neurotransmitter in many brain regions and at nerve-muscle contacts. GABAA receptors (GABAAR) are the targets for many important drugs, including agents active as anti-epileptics, sedatives, and general anesthetics. Nicotinic acetylcholine receptors (nAChR), which are the site of binding of nicotine and are related in structure to GABAARs, modulate the release of neurotransmitters including glutamate and dopamine and are involved in the regulation of sleep, attention, learning, and memory. Dysfunctions of nAChRs are implicated in several pathophysiological conditions including Alzheimer’s and Parkinson’s diseases, and drugs that target nAChRs have potential uses in the treatment of these conditions as well as nicotine addiction. nAChRs on skeletal muscle mediate neural control of muscle contraction, and they are the receptors that are destroyed in an autoimmune disease, myasthenia gravis.
One research area concerns the mode of action of drugs that produce general anesthesia by binding to GABAARs. Anesthetics vary in structure from small volatiles to barbiturates and complex steroids. Studies are underway to determine the number and locations of anesthetic binding sites in GABAARs. Do anesthetics of different chemical classes bind to the same or distinct sites? Why do some barbiturates potentiate the action of GABA and act as anesthetics while others inhibit GABA responses and act as convulsants? An understanding of the diversity of general anesthetic binding sites in GABAARs will provide a basis for the development of anesthetics with fewer undesirable side effects. A second research area concerns the mechanisms of action of drugs that act as potentiators (positive allosteric modulators) of brain or muscle nAChRs. We are developing novel photoreactive general anesthetics and nAChR modulators and use protein chemistry and computational techniques to identify their binding sites in GABAARs and nAChRs, and we use electrophysiological techniques to characterize the functional properties of wild-type and mutant receptors.
Selected recent publications:
1. Jayakar SS, Dailey, WP, Eckenhoff, RG, and Cohen, JB (2013) Identification of propofol binding sites in a nicotinic acetylcholine receptor with a photoreactive propofol analog. J. Biol. Chem. 288: 6167-6189 (PMID: 23300078; PMCID: PMC3585054).
2. Chiara, DC, Jayakar, SS, Zhou, X, Zhang, X, Savechenkov, PY, Bruzik, KS, Miller, KW, and Cohen, JB (2013) Specificity of intersubunit general anesthetic binding sites in the transmembrane domain of the human a1β3g2 GABAA receptor. J. Biol. Chem. 288:19343-19357 (PMID: 23677991; PMCID: PMC3707639)
3. Jayakar, SS, Zhou, X, Savechenkov, PY, Chiara, DC, Desai, R, Bruzik, KS, Miller, KW, and Cohen, JB (2015) Positive and negative allosteric modulation of an α1β3γ2 γ-aminobutyric acid type A (GABAA) receptor by binding to a site in the transmembrane domain at the γ+–β– interface. J. Biol. Chem. 290: 23432-23446 (PMID: 26229099; PMCID: PMC4645599)
4. Hamouda, AK, Deba, F, Wang, ZJ, and Cohen, JB (2016) Photolabeling a nicotinic acetylcholine receptor (nAChR) with an (α4)3(β2)2 nAChR-selective positive allosteric modulator Mol. Pharmacol. 89:575-584 (PMID: 26976945; PMCID: PMC4851301)
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