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.