Jonathan Cohen
Jonathan Cohen, PhD
Bullard Professor of Neurobiology

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. GABAA receptors (GABAAR) are the targets for many important drugs, including agents active as antieptileptics, sedatives, and general anesthetics. Nicotinic acetylcholine receptors (nAcChR) , 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 area of current research 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 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."

researchFigure. A model of the GABAA receptor, including the locations of the binding sites in the extracellular domain for GABA (green) and benzodiazepines (blue) and in the transmembrane domain for general anesthetics (brown, a barbiturate; red, etomidate). (From Chiara et al., J. Biol. Chem. 288: 19343-19357 (2013))

 

"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."

Publications View
Identifying Drugs that Bind Selectively to Intersubunit General Anesthetic Sites in the a1ß3?2 GABAAR Transmembrane Domain.
Authors: Authors: Jayakar SS, Zhou X, Chiara DC, Jarava-Barrera C, Savechenkov PY, Bruzik KS, Tortosa M, Miller KW, Cohen JB.
Mol Pharmacol
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A photoreactive analog of allopregnanolone enables identification of steroid-binding sites in a nicotinic acetylcholine receptor.
Authors: Authors: Yu Z, Chiara DC, Savechenkov PY, Bruzik KS, Cohen JB.
J Biol Chem
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Inhibitable photolabeling by neurosteroid diazirine analog in the ß3-Subunit of human hetereopentameric type A GABA receptors.
Authors: Authors: Wu B, Jayakar SS, Zhou X, Titterton K, Chiara DC, Szabo AL, Savechenkov PY, Kent DE, Cohen JB, Forman SA, Miller KW, Bruzik KS.
Eur J Med Chem
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Etomidate and Etomidate Analog Binding and Positive Modulation of ?-Aminobutyric Acid Type A Receptors: Evidence for a State-dependent Cutoff Effect.
Authors: Authors: McGrath M, Yu Z, Jayakar SS, Ma C, Tolia M, Zhou X, Miller KW, Cohen JB, Raines DE.
Anesthesiology
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Competitive Antagonism of Anesthetic Action at the ?-Aminobutyric Acid Type A Receptor by a Novel Etomidate Analog with Low Intrinsic Efficacy.
Authors: Authors: Ma C, Pejo E, McGrath M, Jayakar SS, Zhou X, Miller KW, Cohen JB, Raines DE.
Anesthesiology
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Enantiomeric barbiturates bind distinct inter- and intrasubunit binding sites in a nicotinic acetylcholine receptor (nAChR).
Authors: Authors: Yu Z, Cohen JB.
J Biol Chem
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Synthesis and pharmacological evaluation of neurosteroid photoaffinity ligands.
Authors: Authors: 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
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General Anesthetic Binding Sites in Human a4ß3d ?-Aminobutyric Acid Type A Receptors (GABAARs).
Authors: Authors: Chiara DC, Jounaidi Y, Zhou X, Savechenkov PY, Bruzik KS, Miller KW, Cohen JB.
J Biol Chem
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Photolabeling a Nicotinic Acetylcholine Receptor (nAChR) with an (a4)3(ß2)2 nAChR-Selective Positive Allosteric Modulator.
Authors: Authors: Hamouda AK, Deba F, Wang ZJ, Cohen JB.
Mol Pharmacol
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Images in Anesthesiology: An Unexpected Embolism during a Craniotomy.
Authors: Authors: Serdiuk A, Khalil F, Cohen JB.
Anesthesiology
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