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The Journal of Neuroscience, September 15, 2000, 20(18):6743-6751

Regulation of Somatodendritic GABA_A Receptor Channels in Rat Hippocampal Neurons: Evidence for a Role of the Small GTPase Rac1

Dieter K. Meyer¹, Claudia Olenik¹, Fred Hofmann¹, Holger Barth¹, Jost Leemhuis¹, Ina Brünig², Klaus Aktories¹, and Wolfgang Nörenberg³

¹ Department of Pharmacology, Albert-Ludwigs-University, 79104 Freiburg, Germany, ² Institute of Pharmacology, University of Zurich, 8057 Zurich, Switzerland, and ³ Department of Pharmacology, University of Leipzig, 04107 Leipzig, Germany

The role of the cytoskeleton in the activity of GABA_A receptors was investigated in cultured hippocampal neurons. Receptor currents were measured with the whole-cell patch-clamp technique during repetitive stimulation with 1 µM muscimol. After destruction of the microtubular system with nocodazol, muscimol-induced currents showed a rundown by 78%. A similar rundown was observed when actin fibers were destroyed with latrunculin B or C2 toxin of Clostridium botulinum. Because the small GTPases of the Rho family RhoA, Rac1, and Cdc42 are known to control the organization of actin fibers, we investigated their possible involvement. Inactivation of the GTPases with clostridial toxins, as well as intracellular application of recombinant Rho GTPases, indicated that active Rac1 was necessary for full GABA_A receptor activity. Immunocytochemical labeling of the receptors showed that the disappearance of receptor clusters in the somatic membrane as induced by muscimol stimulation was enhanced by Rac1 inactivation. It is suggested that Rac1 participates in the regulation of GABA_A receptor clustering and/or recycling.

Key words: GABA_A receptor rundown; actin cytoskeleton; microtubules; hippocampal neurons; Rac1 GTPase; receptor clusters

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20186743-09$05.00/0

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