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Sci. Signal., 10 April 2012
Vol. 5, Issue 219, p. ra29
[DOI: 10.1126/scisignal.2002299]


Direct Binding Between Orai1 and AC8 Mediates Dynamic Interplay Between Ca2+ and cAMP Signaling

Debbie Willoughby1, Katy L. Everett1, Michelle L. Halls1*, Jonathan Pacheco2, Philipp Skroblin3,4, Luis Vaca2, Enno Klussmann4, and Dermot M. F. Cooper1{dagger}

1 Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
2 Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico 04510, Distrito Federal, México.
3 Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.
4 Max-Delbrück-Centrum für Molekulare Medizin, 13125 Berlin, Germany.

* Present address: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia.

Abstract: 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.

{dagger} To whom correspondence should be addressed. E-mail: dmfc2{at}

Citation: D. Willoughby, K. L. Everett, M. L. Halls, J. Pacheco, P. Skroblin, L. Vaca, E. Klussmann, D. M. F. Cooper, Direct Binding Between Orai1 and AC8 Mediates Dynamic Interplay Between Ca2+ and cAMP Signaling. Sci. Signal. 5, ra29 (2012).

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