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The Journal of Neuroscience, August 18, 2004, 24(33):7241-7250; doi:10.1523/JNEUROSCI.1979-04.2004

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Cellular/Molecular
Evidence for Inhibition Mediated by Coassembly of GABA_A and GABA_C Receptor Subunits in Native Central Neurons

Carol J. Milligan,^1 * Noel J. Buckley,^1,2 Maurice Garret,³ Jim Deuchars,¹ and Susan A. Deuchars^1 *

¹School of Biomedical Sciences, University of Leeds, Leeds LS2 9NQ, United Kingdom, ²School of Biochemistry and Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom, and ³Laboratoire de Neurophysiologie, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5543, Universitie de Bordeaux I, Bordeaux, France

Fast inhibition in the nervous system is commonly mediated by GABA_A receptors comprised of 2/2/1 subunits. In contrast, GABA_C receptors containing only subunits (1-3) have been predominantly detected in the retina. However, here using reverse transcription-PCR and in situ hybridization we show that mRNA encoding the 1 subunit is highly expressed in brainstem neurons. Immunohistochemistry localized the 1 subunit to neurons at light and electron microscopic levels, where it was detected at synaptic junctions. Application of the GABA_C receptor agonist cis-4-aminocrotonic acid (100-800 µM) requires the 1 subunit to elicit responses, which surprisingly are blocked independently by antagonists to GABA_A (bicuculline, 10 µM) and GABA_C [(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA); 40-160 µM] receptors. Responses to GABA_C agonists were also enhanced by the GABA_A receptor modulator pentobarbitone (300 µM). Spontaneous and evoked IPSPs were reduced in amplitude but never abolished by TPMPA, but were completely blocked by bicuculline. We therefore tested the hypothesis that GABA_A and GABA_C subunits formed a heteromeric receptor. Immunohistochemistry indicated that 1 and 1 subunits were colocalized at light and electron microscopic levels. Electrophysiology revealed that responses to GABA_C receptor agonists were enhanced by the GABA_A receptor modulator zolpidem (500 nM), which acts on the 1 subunit when the 2 subunit is also present. Finally, coimmunoprecipitation indicated that the 1 subunit formed complexes that also contained1 and 2 subunits. Taken together these separate lines of evidence suggest that the effects of GABA in central neurons can be mediated by heteromeric complexes of GABA_A and GABA_C receptor subunits.

Key words: autonomic; bicuculline; brainstem; GABA; IPSP; preganglionic

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Received July 10, 2003; revised June 28, 2004; accepted June 28, 2004.

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