3-Isobutyl-1-methylxanthine inhibits sustained calcium current independently of cyclic AMP in neuronal and endocrine cells.

The effect of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) on the voltage-dependent calcium current was studied in the clonal pituitary cell line GH3 by whole-cell patch-clamp techniques. It was found that IBMX reversibly inhibited the sustained calcium current (Ki, 1.25 mM), whereas there was no effect on the transient current. IBMX increased the inactivation rate of the sustained current without altering the voltage of activation. Vasoactive intestinal peptide, an agent known to increase cAMP, was without effect on the calcium current. The effect of IBMX was not altered by pretreating the cells with pertussis toxin or by including either cAMP or protein kinase inhibitor in the intracellular solution. The order of potency for several xanthine derivatives was IBMX > theophylline > caffeine > xanthine. The effect of IBMX on calcium current was also observed in three additional neuronal and endocrine cell lines (PC12, SY5Y, and RINm5f). These results indicate that IBMX inhibits sustained voltage-dependent calcium current by a mechanism independent of alterations in cAMP levels.