title: Direct binding between Orai1 and AC8 mediates dynamic interplay between Ca2+ and cAMP signaling.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
authors.forename: Debbie
authors.initials: D
authors.lastname: Willoughby
authors.forename: Katy L
authors.initials: KL
authors.lastname: Everett
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Halls
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pacheco
authors.forename: Philipp
authors.initials: P
authors.lastname: Skroblin
authors.forename: Luis
authors.initials: L
authors.lastname: Vaca
authors.forename: Enno
authors.initials: E
authors.lastname: Klussmann
authors.forename: Dermot M F
authors.initials: DM
authors.lastname: Cooper
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007477:Ions; D008164:Luminescent Proteins / Q000378:metabolism; D000071740:ORAI1 Protein; D017434:Protein Structure, Tertiary
chemical_list: D001426:Bacterial Proteins; D015220:Calcium Channels; D007477:Ions; D008164:Luminescent Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C054562:yellow fluorescent protein, Bacteria; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C118292:adenylyl cyclase 8; D002118:Calcium