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The Journal of Neuroscience, August 31, 2005, 25(35):8056-8065; doi:10.1523/JNEUROSCI.0348-05.2005

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Cellular/Molecular
Structural Determinants of Benzodiazepine Allosteric Regulation of GABA_A Receptor Currents

Dorothy M. Jones-Davis,¹ Luyan Song,² Martin J. Gallagher,² and Robert L. Macdonald^2,3,4

¹Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan 48104-1687, and Departments of ²Neurology, ³Molecular Physiology and Biophysics, and ⁴Pharmacology, Vanderbilt University, Nashville, Tennessee 37212

Benzodiazepine enhancement of GABA_A receptor current requires a subunit, and replacement of the subunit by the subunit abolishes benzodiazepine enhancement. Although it has been demonstrated that benzodiazepines bind to GABA_A receptors at the junction between and subunits, the structural basis for the coupling of benzodiazepine binding to allosteric enhancement of the GABA_A receptor current is unclear. To determine the structural basis for this coupling, the present study used a chimera strategy, using 2L- GABA_A receptor subunit chimeras coexpressed with1 and3 subunits in human embryonic kidney 293T cells. Different domains of the 2L subunit were replaced by subunit sequence, and diazepam sensitivity was determined. Chimeric subunits revealed two areas of interest: domain 1 in transmembrane domain 1 (M1) and domain 2 in the C-terminal portion of transmembrane domain 2 (M2) and the M2–M3 extracellular loop. In those domains, site-directed mutagenesis demonstrated that the following two groups of residues were involved in benzodiazepine transduction of current enhancement: residues Y235, F236, T237 in M1; and S280, T281, I282 in M2 as well as the entire M2–M3 loop. These results suggest that a pocket of residues may transduce benzodiazepine binding to increased gating. Benzodiazepine transduction involves a group of residues that connects the N terminus and M1, and another group of residues that may facilitate an interaction between the N terminus and the M2 and M2–M3 loop domains.

Key words: GABA_A receptors; benzodiazepines; ion channel structure–function; binding–gating transduction; coupling; receptor chimera

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Received June 2, 2004; revised July 11, 2005; accepted July 13, 2005.

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