Abstract
Interleukin-1β (IL-1β), 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-1β action on the γ-aminobutyric acid type A (GABAA) inhibitory neurotransmitter receptor was investigated in whole cell patch-clamped cultured hippocampal neurons. Application of IL-1β 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-1β concentration- and time-dependent and was prevented by a specific IL-1β type I receptor antagonist. No significant changes in current kinetics or reversal potential were observed. The IL-1β 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-1β 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.
Footnotes
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Send reprint requests to: Dr. Jay Yang, Department of Anesthesiology, Box 604, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642. E-mail: jyang{at}anes.rochester.edu
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1 This work was supported by National Institutes of Health Grants GM52325 (to J.Y.) and T32-DA07232 (to S.M.).
- Abbreviations:
- IL-1β
- interleukin-1β
- IL-1RI
- interleukin-1 type I receptor
- IL-1Ra
- interleukin-1 receptor antagonist
- Erev
- reversal potential
- GABA
- γ-aminobutyric acid
- GABAA
- γ-aminobutyric acid type A
- PKA
- cAMP-dependent protein kinase
- PKC
- protein kinase C
- β-PMA
- β-phorbol 12-myristate 13-acetate
- H-7
- 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine
- PBST
- PBS with 0.2% Tween 20
- NGS
- normal goat serum
- Received August 9, 1999.
- Accepted October 12, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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