Inhibition of human TREK-1 channels by caffeine and theophylline.
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 (IC(50)) for caffeine and theophylline were 377+/-54microM and 486+/-76microM, respectively. Caffeine and theophylline depolarized the membrane potential of CHO(TREK-1) cells in a reversible and concentration-dependent manner. Inhibition by caffeine (5mM) and theophylline (2mM) 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-1 channels and consequent membrane depolarization may contribute to the convulsive seizures induced by toxic levels of caffeine and theophylline.
Harinath
S
S
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
Sikdar
S K
SK
D000818:Animals; D016466:CHO Cells; D002110:Caffeine / Q000494:pharmacology*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009154:Mutation / Q000187:drug effects / Q000502:physiology; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013806:Theophylline / Q000494:pharmacology*
D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1; D002110:Caffeine; D013806:Theophylline