Modulation of dihydropyridine-sensitive calcium channels in Drosophila by a cAMP-mediated pathway

Drosophila has proved to be a valuable system for studying the structure an d function of ion channels. However, relatively little is known about the r egulation of ion channels, particularly that of Ca2+ channels, in Drosophil a. Physiological and pharmacological differences between invertebrate and m ammalian L-type Ca2+ channels raise questions on the extent of conservation of Ca2+ channel modulatory pathways. We have examined the role of cyclic a denosine monophosphate (cAMP) cascade in modulating the dihydropyridine (DH P)-sensitive Ca2+ channels in the larval muscles of Drosophila, using mutat ions and drugs that disrupt specific steps in this pathway. The L-tSpe (DHP -sensitive) Ca2+ channel current was increased in the dunce mutants, which have high cAMP concentration owing to cAMP-specific phosphodiesterase (PDE) disruption. The current was decreased in the rutabaga mutants, where adeny lyl cyclase (AC) activity is altered thereby decreasing the cAMP concentrat ion. The dunce effect was mimicked by 8-Br-cAMP, a cAMP analog, and IBMX, a PDE inhibitor. The rutabaga effect was rescued by forskolin, an AC activat or. H-89, an inhibitor of protein kinase-A (PKA), reduced the current and i nhibited the effect of 8-Br-cAMP. The data suggest modulation of L-type Ca2 + channels of Drosophila via a cAMP-PKA mediated pathway. While there are d ifferences in L-type channels, as well as in components of cAMP cascade, be tween Drosophila and vertebrates, main features of the modulatory pathway h ave been conserved. The data also raise questions on the likely role of DHP sensitive Ca2+ channel modulation in synaptic plasticity, and learning and memory, processes disrupted by the dnc and the rut mutations. (C) 1999 Joh n Wiley & Sons, Inc.