Emergence of Orai3 activity during cardiac hypertrophy

Youakim Saliba, Mathilde Keck, Alexandre Marchand, Fabrice Atassi, Aude Ouillé, Olivier Cazorla, Mohamed Trebak, Catherine Pavoine, Alain Lacampagne, Jean Sébastien Hulot, Nassim Farès, Jérémy Fauconnier, Anne Marie Lompré

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Aims Stromal interaction molecule 1 (STIM1) has been shown to control a calcium (Ca2+) influx pathway that emerges during the hypertrophic remodelling of cardiomyocytes. Our aim was to determine the interaction of Orai1 and Orai3 with STIM1 and their role in the constitutive store-independent and the store-operated, STIM1-dependent, Ca2+ influx in cardiomyocytes. Methods and results We characterized the expression profile of Orai proteins and their interaction with STIM1 in both normal and hypertrophied adult rat ventricular cardiomyocytes. Orai1 and 3 protein levels were unaltered during the hypertrophic process and both proteins co-immunoprecipitated with STIM1. The level of STIM1 and Orai1 were significantly greater in the macromolecular complex precipitated by the Orai3 antibody in hypertrophied cardiomyocytes. We then used a non-viral method to deliver Cy3-tagged siRNAs in vivo to adult ventricular cardiomyocytes and silence Orai channel candidates. Cardiomyocytes were subsequently isolated then the voltage-independent, i.e. store-independent and storeoperated Ca2+ entries were measured on Fura-2 AM loaded Cy3-labelled and control isolated cardiomyocytes. The whole cell patch-clamp technique was used to measure Orai-mediated currents. Specific Orai1 and Orai3 knockdown established Orai3, but not Orai1, as the critical partner of STIM1 carrying these voltage-independent Ca2+ entries in the adult hypertrophied cardiomyocytes. Orai3 also drove an arachidonic acid-activated inward current. Conclusion Cardiac Orai3 is the essential partner of STIM1 and drives voltage-independent Ca2+ entries in adult cardiomyocytes. Arachidonic acid-activated currents, which are supported by Orai3, are present in adult cardiomyocytes and increased during hypertrophy.

Original languageEnglish (US)
Pages (from-to)248-259
Number of pages12
JournalCardiovascular Research
Volume105
Issue number3
DOIs
StatePublished - 2015

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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