Hippocampal Neurons Express a Calcineurin-Activated Adenylyl Cyclase

Abstract

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.