The role of Ca2+/calmodulin-stimulable adenylyl cyclases as molecular coincidence detectors in memory formation

Evidence from systems as diverse as mollusks, insects and mammals has revealed that adenylyl cyclase, cyclic adenosine 3′,5′-monophosphate (cAMP) cascade, cAMP-dependent protein kinases and their substrates are required for the cellular events underlying the short-term and long-term forms of memory. In Aplysia and Drosophila models, the coincident activation of independent paths converge to produce a synergistic activation of Ca²⁺/calmodulin-stimulable adenylyl cyclase, thereby enhancing the cAMP level that appears as the primary mediator of downstream events that strengthen enduring memory. In mammals, in which long-term memories require hippocampal function, our understanding of the role of adenylyl cyclases is still fragmentary. Of the differently regulated isoforms present in the hippocampus, the susceptibility of type 1 and type 8 to stimulation by the complex Ca²⁺/calmodulin and their expression in the hippocampus suggest a role for these two isoforms as a molecular coincidence device for hippocampus-related memory function. Here, we review the key features of Ca²⁺/calmodulin stimulable adenylyl cyclases, as well as the involvement of cAMP-regulated signaling pathway in the processes of learning and memory.