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Recent studies have suggested that STIM1 plays a role in pathological hypertrophy; however, the physiological role of STIM1 in the heart is not well understood. We have shown that mice with a cardiomyocyte deletion of STIM1 (<jats:sup>cr<\/jats:sup>STIM1<jats:sup>\u2212\/\u2212<\/jats:sup>) develop ER stress, mitochondrial, and metabolic abnormalities, and dilated cardiomyopathy. However, the specific signaling pathways and kinases regulated by STIM1 are largely unknown. Therefore, we used a discovery\u2010based kinomics approach to identify kinases differentially regulated by STIM1. Twelve\u2010week male control and <jats:sup>cr<\/jats:sup>STIM1<jats:sup>\u2212\/\u2212<\/jats:sup> mice were injected with saline or phenylephrine (PE, 15\u00a0mg\/kg, s.c, 15\u00a0min), and hearts obtained for analysis of the Serine\/threonine kinome. Primary analysis was performed using BioNavigator 6.0 (PamGene), using scoring from the Kinexus PhosphoNET database and GeneGo network modeling, and confirmed using standard immunoblotting. Kinomics revealed significantly lower PKG and protein kinase C (PKC) signaling in the hearts of the <jats:sup>cr<\/jats:sup>STIM1<jats:sup>\u2212\/\u2212<\/jats:sup> in comparison to control hearts, confirmed by immunoblotting for the calcium\u2010dependent PKC isoform PKC\u03b1 and its downstream target MARCKS. Similar reductions in <jats:sup>cr<\/jats:sup>STIM1<jats:sup>\u2212\/\u2212<\/jats:sup> hearts were found for the kinases: MEK1\/2, AMPK, and PDPK1, and in the activity of the Ca<jats:sup>2+<\/jats:sup>\u2010dependent phosphatase, calcineurin. Electrocardiogram analysis also revealed that <jats:sup>cr<\/jats:sup>STIM1<jats:sup>\u2212\/\u2212<\/jats:sup> mice have significantly lower HR and prolonged QT interval. In conclusion, we have shown several calcium\u2010dependent kinases and phosphatases are regulated by STIM1 in the adult mouse heart. This has important implications in understanding how STIM1 contributes to the regulation of cardiac physiology and pathophysiology.<\/jats:p>","DOI":"10.14814\/phy2.15177","type":"journal-article","created":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T15:24:06Z","timestamp":1645197846000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cardiomyocyte stromal interaction molecule 1 is a key regulator of Ca<sup>2+<\/sup>\u2010dependent kinase and phosphatase activity in the mouse heart"],"prefix":"10.14814","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9302-6044","authenticated-orcid":false,"given":"Helen E.","family":"Collins","sequence":"first","affiliation":[{"name":"Division of Environmental Medicine Department of Medicine University of Louisville  Louisville Kentucky 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