Hippocampal neurons express a calcineurin-activated adenylyl cyclase.

Ca2+-stimulated adenylyl cyclases are important for several forms of neuroplasticity because they couple activity-dependent Ca2+ increases to cAMP in neurons. For example, the calmodulin-stimulated adenylyl cyclases, AC1 and AC8, are required for hippocampus-dependent memory and long-lasting long-term potentiation. To identify other mechanisms for Ca2+ stimulation of adenylyl cyclases, cultured hippocampal neurons from transgenic mice lacking both AC1 and AC8 [double knock-out (DKO) mice] were analyzed for Ca2+ stimulation of intracellular cAMP. Surprisingly, neurons from DKO mice showed significant Ca2+-stimulated cAMP accumulation that was blocked by inhibitors of calcineurin [PP2B (protein phosphatase 2B)], a Ca2+-activated protein phosphatase. Analysis of cultured neurons from calcineurin(-/-) mice confirmed that hippocampal neurons exhibit a calcineurin-dependent cAMP increase, which may contribute to some forms of neuroplasticity.