RT Journal Article SR Electronic T1 Direct Binding Between Orai1 and AC8 Mediates Dynamic Interplay Between Ca2+ and cAMP Signaling JF Science Signaling JO Sci. Signal. FD American Association for the Advancement of Science SP ra29 OP ra29 DO 10.1126/scisignal.2002299 VO 5 IS 219 A1 Willoughby, Debbie A1 Everett, Katy L. A1 Halls, Michelle L. A1 Pacheco, Jonathan A1 Skroblin, Philipp A1 Vaca, Luis A1 Klussmann, Enno A1 Cooper, Dermot M. F. YR 2012 UL http://stke.sciencemag.org/content/5/219/ra29.abstract AB The interplay between calcium ion (Ca2+) and cyclic adenosine monophosphate (cAMP) signaling underlies crucial aspects of cell homeostasis. The membrane-bound Ca2+-regulated adenylyl cyclases (ACs) are pivotal points of this integration. These enzymes display high selectivity for Ca2+ entry arising from the activation of store-operated Ca2+ (SOC) channels, and they have been proposed to functionally colocalize with SOC channels to reinforce crosstalk between the two signaling pathways. Using a multidisciplinary approach, we have identified a direct interaction between the amino termini of Ca2+-stimulated AC8 and Orai1, the pore component of SOC channels. High-resolution biosensors targeted to the AC8 and Orai1 microdomains revealed that this protein-protein interaction is responsible for coordinating subcellular changes in both Ca2+ and cAMP. The demonstration that Orai1 functions as an integral component of a highly organized signaling complex to coordinate Ca2+ and cAMP signals underscores how SOC channels can be recruited to maximize the efficiency of the interplay between these two ubiquitous signaling pathways.