The native ORAI channel trio underlies the diversity of Ca2+ signaling events

Ryan E. Yoast, Scott M. Emrich, Xuexin Zhang, Ping Xin, Martin T. Johnson, Adam J. Fike, Vonn Walter, Nadine Hempel, David I. Yule, James Sneyd, Donald L. Gill and Mohamed Trebak ()
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Ryan E. Yoast: The Pennsylvania State University College of Medicine
Scott M. Emrich: The Pennsylvania State University College of Medicine
Xuexin Zhang: The Pennsylvania State University College of Medicine
Ping Xin: The Pennsylvania State University College of Medicine
Martin T. Johnson: The Pennsylvania State University College of Medicine
Adam J. Fike: The Pennsylvania State University College of Medicine
Vonn Walter: The Pennsylvania State University College of Medicine
Nadine Hempel: Penn State Cancer Institute and The Pennsylvania State University College of Medicine
David I. Yule: University of Rochester Medical Center School of Medicine and Dentistry
James Sneyd: The University of Auckland
Donald L. Gill: The Pennsylvania State University College of Medicine
Mohamed Trebak: The Pennsylvania State University College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract The essential role of ORAI1 channels in receptor-evoked Ca2+ signaling is well understood, yet little is known about the physiological activation of the ORAI channel trio natively expressed in all cells. The roles of ORAI2 and ORAI3 have remained obscure. We show that ORAI2 and ORAI3 channels play a critical role in mediating the regenerative Ca2+ oscillations induced by physiological receptor activation, yet ORAI1 is dispensable in generation of oscillations. We reveal that ORAI2 and ORAI3 channels multimerize with ORAI1 to expand the range of sensitivity of receptor-activated Ca2+ signals, reflecting their enhanced basal STIM1-binding and heightened Ca2+-dependent inactivation. This broadened bandwidth of Ca2+ influx is translated by cells into differential activation of NFAT1 and NFAT4 isoforms. Our results uncover a long-sought role for ORAI2 and ORAI3, revealing an intricate control mechanism whereby heteromerization of ORAI channels mediates graded Ca2+ signals that extend the agonist-sensitivity to fine-tune transcriptional control.

Date: 2020
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DOI: 10.1038/s41467-020-16232-6

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