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Inhibition of human TREK-1 channels by caffeine and theophylline

Harinath, S and Sikdar, SK (2005) Inhibition of human TREK-1 channels by caffeine and theophylline. In: Epilepsy Research, 64 (3). pp. 127-135.


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Caffeine (1,3,7-trimethylxanthine) and theophylline(1,3-dimethylxanthine) are used for therapeutic purposes and can cause life-threatening convulsive seizures due to systemic toxicity. The mechanisms for the epileptogenicity of caffeine and theophylline are not clear. TWIK-related K+ channels (TREK-1) are highly expressed in the human central nervous system and have a major role in the control of neuronal excitability by regulating the resting membrane potential.In view of their physiological significance, inhibition of TREK-1 channels may be implicated in caffeine- and theophylline-induced seizures. We thus investigated, using whole-cell patch-clamp technique,modulation of hTREK-1 channels expressed in Chinese hamster ovary (CHO)cells by caffeine and theophylline. Caffeine and theophylline produced reversible inhibition of TREK-1 channels in a concentration-dependent manner. The half-maximal inhibitory concentrations (IC50) for caffeine and theophylline were 377 +/- 54 mu M and 486 +/- 76 mu M,respectively. Caffeine and theophylline depolarized the membrane potential of CHOTREK-1 cells in a reversible and concentration-dependent manner. Inhibition by caffeine (5 mM) and theophylline (2 mM) was attenuated in TREK-1 channels with mutation of the PKA consensus sequence at serine 348, suggesting the involvement of cAMP/PKA pathway in the inhibitory process. Inhibition of TREK-1channels and consequent membrane depolarization may contribute to the convulsive seizures induced by toxic levels of caffeine and theophylline.

Item Type: Journal Article
Additional Information: Copyright for this article belongs to Elsevier.
Keywords: Caffeine;Theophylline;Seizures;TREK-1 channel;Whole-cell patch-clamp
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Depositing User: B.S Priyanka
Date Deposited: 31 Aug 2005
Last Modified: 19 Sep 2010 04:19
URI: http://eprints.iisc.ac.in/id/eprint/3579

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