Organization of cAMP signalling microdomains for optimal regulation by Ca²⁺ entry

Cross-talk between cAMP and Ca²⁺ signalling pathways plays a critical role in cellular homoeostasis. Several AC (adenylate cyclase) isoforms, catalysing the production of cAMP from ATP, display sensitivity to submicromolar changes in intracellular Ca²⁺ and, as a consequence, are key sites for Ca²⁺ and cAMP interplay. Interestingly, these Ca²⁺-regulated ACs are not equally responsive to equivalent Ca²⁺ rises within the cell, but display a remarkable selectivity for regulation by SOCE (store-operated Ca²⁺ entry). Over the years, considerable efforts at investigating this phenomenon have provided indirect evidence of an intimate association between Ca²⁺-sensitive AC isoforms and sites of SOCE. Now, recent identification of the molecular components of SOCE [namely STIM1 (stromal interaction molecule 1) and Orai1], coupled with significant advances in the generation of high-resolution targeted biosensors for Ca²⁺ and cAMP, have provided the first detailed insight into the organization of the cellular microdomains associated with Ca²⁺-regulated ACs. In the present review, I summarize the findings that have helped to provide our most definitive understanding of the selective regulation of cAMP signalling by SOCE.