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Photochemical Proteolysis of an Unstructured Linker of the GABAAR Extracellular Domain Prevents GABA but Not Pentobarbital Activation

Hanek, Ariele P. and Lester, Henry A. and Dougherty, Dennis A. (2010) Photochemical Proteolysis of an Unstructured Linker of the GABAAR Extracellular Domain Prevents GABA but Not Pentobarbital Activation. Molecular Pharmacology, 78 (1). pp. 29-35. ISSN 0026-895X. PMCID PMC2912059. doi:10.1124/mol.109.059832.

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The GABA type A receptor (GABAAR) is the major inhibitory receptor in the mammalian central nervous system and the target of numerous pharmaceuticals. The α-subunit of these pentameric Cys-loop neurotransmitter-gated ion channels contributes to the binding of both GABA and allosteric modulators such as the benzodiazepines, suggesting a role for this subunit in the conformational changes associated with activation of the receptor. Herein we use the nonsense suppression methodology to incorporate a photoactivatable unnatural amino acid and photochemically cleave the backbone of the α subunit of the α_1β_2 GABA_AR in a linker region that is believed to span the subunit. Proteolytic cleavage impairs GABA but not pentobarbital activation, strongly suggesting that conformational changes involving this linker region are critical to the GABA activation pathway.

Item Type:Article
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URLURL TypeDescription DOIArticle CentralArticle
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2010 The American Society for Pharmacology and Experimental Therapeutics. Received July 27, 2009; accepted April 2, 2010. Published online before print April 2, 2010. We thank Dr. Sarah Lummis for providing the human α1 and β2S GABAAR genes, for providing a GABAAR homology model, and for help in experiment design. In addition, we thank Angela Blum for aid in the synthesis of Npg and the preparation of the amino acid for coupling to dCA. This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS34407, NS11756]. This work was presented previously: Hanek AP (2009) Chemical-scale investigations of the Cys-loop neurotransmitter gated ion channel. Ph.D. thesis. California Institute of Technology, Pasadena, CA.
Funding AgencyGrant Number
NIH National Institute of Neurological Disorders and StrokeNS34407
NIH National Institute of Neurological Disorders and StrokeNS11756
Issue or Number:1
PubMed Central ID:PMC2912059
Record Number:CaltechAUTHORS:20100709-141019159
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:18974
Deposited By: Tony Diaz
Deposited On:09 Jul 2010 22:53
Last Modified:08 Nov 2021 23:48

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