Evidence from invertebrate systems including Aplysia and Drosophila, as well as studies carried out with mammalian brain, suggests that Ca2+-sensitive adenylyl cyclases may be important for long-term synaptic changes and learning and memory. Furthermore, some forms of long-term potentiation (LTP) in the hippocampus elevate cyclic AMP (cAMP) signals, and activation of adenylyl cyclases and cAMP-dependent protein kinase may be required for late stages of LTP. We propose that long-term changes in neurons and at synapses may require synergism between the cAMP and Ca2+ signal transduction systems which regulates transcription and synthesis of specific proteins required for long-term synaptic changes. During LTP, protein kinase C is activated and intraccllular Ca2+ increases. We hypothesize that the calmodulin (CaM)-regulated adenylyl cyclases may be activated during LTP because of increases in intracellular Ca2+, release of free CaM from neuromodulin, activation by protein kinase C, release of neurotransmitters, or a combination of these events. Synergistic activation of CaM-sensitive adenylyl cyclases may produce a robust or prolonged cAMP signal required for transcriptional control. Furthermore, the coupling of the Ca2+ and cAMP systems may provide positive feedback regulation of Ca2+ channels by cAMP-dependent protein kinase