VOLTAGE-SENSITIVE ADENYLYL-CYCLASE ACTIVITY IN CULTURED NEURONS - A CALCIUM-INDEPENDENT PHENOMENON

Catalytic subunits of mammalian adenylyl cyclases have been proposed t o contain 12 transmembrane domains, a property shared with some voltag e-sensitive ion channels. Here we report that adenylyl cyclase activit y in cerebellar neurons is synergistically stimulated by depolarizing agents and beta-adrenergic receptor activation. This phenomenon is Ca2 +-independent and not attributable to Ca2+-stimulated adenylyl cyclase activity. Cholera toxin and forskolin also synergistically stimulate adenylyl cyclase activity in combination with depolarizing agents. We hypothesize that conformational changes in the catalytic subunit of th e enzymes caused by changes in the membrane potential may enhance stim ulation of adenylyl cyclases by the guanylyl nucleotide stimulatory pr otein. This novel mechanism for regulation of adenylyl cyclases genera tes robust cAMP signals that may contribute to various neuromodulatory events including some forms of neuroplasticity.