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

Debbie Willoughby¹, Katy L. Everett¹, Michelle L. Halls^1*, Jonathan Pacheco², Philipp Skroblin^3,4, Luis Vaca², Enno Klussmann⁴, and Dermot M. F. Cooper¹

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.

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.

To whom correspondence should be addressed. E-mail: dmfc2{at}cam.ac.uk

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