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Vol. 292, Issue 2, 497-504, February 2000

Interleukin-1beta Inhibits gamma -Aminobutyric Acid Type A (GABAA) Receptor Current in Cultured Hippocampal Neurons

Sam Wang, Qing Cheng, Sundeep Malik and Jay Yang

Departments of Anesthesiology (S.W., J.Y.) and Pharmacology/Physiology (Q.C., S.M., J.Y.), University of Rochester Medical Center, Rochester, New York.

Interleukin-1beta (IL-1beta ), a polypeptide immune mediator, is induced within the central nervous system in response to a variety of pathological stimuli, including systemic infection, hypoxia, brain trauma, and seizure. IL-1beta action on the gamma -aminobutyric acid type A (GABAA) inhibitory neurotransmitter receptor was investigated in whole cell patch-clamped cultured hippocampal neurons. Application of IL-1beta at concentrations encountered in pathophysiological conditions (1-10 ng/ml; 59-590 pM) irreversibly decreased the peak magnitude of current elicited by 30 µM GABA. Current inhibition was IL-1beta concentration- and time-dependent and was prevented by a specific IL-1beta type I receptor antagonist. No significant changes in current kinetics or reversal potential were observed. The IL-1beta depression of GABA current was inhibited by high concentrations of nonspecific kinase inhibitors staurosporine (500 nM) and 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7; 50 µM), but not by a protein kinase C selective inhibitor calphostin C (5 µM). We conclude that IL-1beta inhibits GABAA receptor function in hippocampal neurons by the involvement of an unidentified kinase. This blockade of the GABAA inhibitory neurotransmitter receptor may underlie the central nervous system hyperexcitability seen in many pathophysiological conditions.

0022-3565/00/2922-0497$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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