Caffeine-induced inhibition of inositol(1,4,5)-trisphosphate-gated calcium channels from cerebellum

Effects of the xanthine drug caffeine on inositol (1,4,5)-trisphosphate (InsP₃)-gated calcium (Ca) channels from canine cerebellum were studied using single channels incorporated into planar lipid bilayers. Caffeine, used widely as an agonist of ryanodine receptors, inhibited the activity of InsP₃-gated Ca channels in a noncooperative fashion with half-inhibition at 1.64 mM caffeine. The frequency of channel openings was decreased more than threefold after addition of 5 mM caffeine; there was only a small effect on mean open time of the channels, and the single channel conductance was unchanged. Increased InsP₃ concentration overcame the inhibitory action of caffeine, but caffeine did not reduce specific [³H]InsP₃ binding to the receptor. The inhibitory action of caffeine on InsP₃ receptors suggests that the action of caffeine on the intracellular Ca pool must be interpreted with caution when both ryanodine receptors and InsP₃ receptors are present in the cell.