Jonathan Cohen
Professor
Department of Neurobiology
Harvard Medical School
United States of America
Biography
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 antieptileptics, 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.
Research Interest
Cell Biology of Neurons & Glia Development & Plasticity Gene Expression Neuropathology & Disease Neuropharmacology & Neurochemistry Receptors & Ion Channels Synapse Function & Plasticity Systems & Integrative Neuroscience
Publications
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Multiple propofol-binding sites in a γ-aminobutyric acid type A receptor (GABAAR) identified using a photoreactive propofol analog. Jayakar SS, Zhou X, Chiara DC, Dostalova Z, Savechenkov PY, Bruzik KS, Dailey WP, Miller KW, Eckenhoff RG, Cohen JB. J Biol Chem. 2014 Oct 3;289(40):27456-68. doi: 10.1074/jbc.M114.581728. Epub 2014 Aug 1.
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Use of miRNA response sequences to block off-target replication and increase the safety of an unattenuated, glioblastoma-targeted oncolytic HSV. Mazzacurati L, Marzulli M, Reinhart B, Miyagawa Y, Uchida H, Goins WF, Li A, Kaur B, Caligiuri M, Cripe T, Chiocca EA, Amankulor N, Cohen JB, Glorioso JC, Grandi P. Mol Ther. 2015 Jan;23(1):99-107. doi: 10.1038/mt.2014.177. Epub 2014 Sep 9. Erratum in: Mol Ther. 2015 Jan;23(1):215. Chiocca, Nino [corrected to Chiocca, Ennio A].
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Use of miRNA Response Sequences to Block Off-target Replication and Increase the Safety of an Unattenuated, Glioblastoma-targeted Oncolytic HSV. Mazzacurati L, Marzulli M, Reinhart B, Miyagawa Y, Uchida H, Goins WF, Li A, Kaur B, Caligiuri M, Cripe T, Chiocca N, Amankulor N, Cohen JB, Glorioso JC, Grandi P. Mol Ther. 2015 Jan;23(1):99-107. doi: 10.1038/mt.2014.177. Epub 2016 Dec 1.
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Desformylflustrabromine (dFBr) and [3H]dFBr-Labeled Binding Sites in a Nicotinic Acetylcholine Receptor. Hamouda AK, Wang ZJ, Stewart DS, Jain AD, Glennon RA, Cohen JB. Mol Pharmacol. 2015 Jul;88(1):1-11. doi: 10.1124/mol.115.098913. Epub 2015 Apr 13. Erratum in: Mol Pharmacol. 2016 Jan;89(1):141.
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CAR-Engineered NK Cells Targeting Wild-Type EGFR and EGFRvIII Enhance Killing of Glioblastoma and Patient-Derived Glioblastoma Stem Cells. Han J, Chu J, Keung Chan W, Zhang J, Wang Y, Cohen JB, Victor A, Meisen WH, Kim SH, Grandi P, Wang QE, He X, Nakano I, Chiocca EA, Glorioso JC 3rd, Kaur B, Caligiuri MA, Yu J. Sci Rep. 2015 Jul 9;5:11483. doi: 10.1038/srep11483.
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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. Jayakar SS, Zhou X, Savechenkov PY, Chiara DC, Desai R, Bruzik KS, Miller KW, Cohen JB. J Biol Chem. 2015 Sep 18;290(38):23432-46. doi: 10.1074/jbc.M115.672006. Epub 2015 Jul 30.
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De novo CD5+ diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter, rituximab treated cohort. Alinari L, Gru A, Quinion C, Huang Y, Lozanski A, Lozanski G, Poston J, Venkataraman G, Oak E, Kreisel F, Park SI, Matthews S, Abramson JS, Iris Lim H, Martin P, Cohen JB, Evens A, Al-Mansour Z, Singavi A, Fenske TS, Blum KA. Am J Hematol. 2016 Jun;91(4):395-9. doi: 10.1002/ajh.24299.
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Photolabeling a Nicotinic Acetylcholine Receptor (nAChR) with an (α4)3(β2)2 nAChR-Selective Positive Allosteric Modulator. Hamouda AK, Deba F, Wang ZJ, Cohen JB. Mol Pharmacol. 2016 May;89(5):575-84. doi: 10.1124/mol.116.103341. Epub 2016 Mar 14.
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Synthesis and pharmacological evaluation of neurosteroid photoaffinity ligands. Savechenkov PY, Chiara DC, Desai R, Stern AT, Zhou X, Ziemba AM, Szabo AL, Zhang Y, Cohen JB, Forman SA, Miller KW, Bruzik KS. Eur J Med Chem. 2017 Aug 18;136:334-347. doi: 10.1016/j.ejmech.2017.04.043. Epub 2017 Apr 21.
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General Anesthetic Binding Sites in Human α4β3δ γ-Aminobutyric Acid Type A Receptors (GABAARs). Chiara DC, Jounaidi Y, Zhou X, Savechenkov PY, Bruzik KS, Miller KW, Cohen JB. J Biol Chem. 2016 Dec 16;291(51):26529-26539. Epub 2016 Nov 7.
