Direct binding between Orai1 and AC8 mediates dynamic interplay between Ca2+ and cAMP signaling

• Published in: Science signaling Vol. 5; no. 219; p. ra29
• Main Authors: Willoughby, Debbie, Everett, Katy L, Halls, Michelle L, Pacheco, Jonathan, Skroblin, Philipp, Vaca, Luis, Klussmann, Enno, Cooper, Dermot M F
• Format: Journal Article
• Language: English
• Published: United States 10.04.2012
• Subjects: Adenylyl Cyclases - metabolism; Bacterial Proteins - metabolism; Calcium - metabolism; Calcium Channels - chemistry; Calcium Channels - metabolism; Cyclic AMP - metabolism; Fluorescence Resonance Energy Transfer; HEK293 Cells; Homeostasis; Humans; Ions; Luminescent Proteins - metabolism; ORAI1 Protein; Protein Structure, Tertiary
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.2002299

The interplay between calcium ion (Ca(2+)) and cyclic adenosine monophosphate (cAMP) signaling underlies crucial aspects of cell homeostasis. The membrane-bound Ca(2+)-regulated adenylyl cyclases (ACs) are pivotal points of this integration. These enzymes display high selectivity for Ca(2+) entry arising from the activation of store-operated Ca(2+) (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 Ca(2+)-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 Ca(2+) and cAMP. The demonstration that Orai1 functions as an integral component of a highly organized signaling complex to coordinate Ca(2+) and cAMP signals underscores how SOC channels can be recruited to maximize the efficiency of the interplay between these two ubiquitous signaling pathways.