Key result
Cardiomyocyte deletion of STIM1 in mice significantly reduced PKG and PKC signaling, along with calcineurin activity, resulting in lower heart rate and prolonged QT interval.
Why the study?
The physiological role of STIM1 in the heart and the specific signaling pathways and kinases it regulates were largely unknown.
Cardiomyocyte STIM1 is a critical regulator of multiple calcium-dependent kinases and phosphatases, impacting cardiac electrophysiology even prior to overt structural remodeling.
Stromal interaction molecule 1 (STIM1) is a major regulator of store‐operated calcium entry in non‐excitable cells. 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 ( cr STIM1 −/− ) 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‐based kinomics approach to identify kinases differentially regulated by STIM1. Twelve‐week male control and cr STIM1 −/− mice were injected with saline or phenylephrine (PE, 15 mg/kg, s.c, 15 min), 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 cr STIM1 −/− in comparison to control hearts, confirmed by immunoblotting for the calcium‐dependent PKC isoform PKCα and its downstream target MARCKS. Similar reductions in cr STIM1 −/− hearts were found for the kinases: MEK1/2, AMPK, and PDPK1, and in the activity of the Ca 2+ ‐dependent phosphatase, calcineurin. Electrocardiogram analysis also revealed that cr STIM1 −/− mice have significantly lower HR and prolonged QT interval. In conclusion, we have shown several calcium‐dependent 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.
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Collins et al. (2022) studied Cardiac physiology and pathophysiology. Cardiomyocyte-restricted deletion of STIM1 (crSTIM1-/-) vs. Littermate controls was evaluated on Serine/threonine kinome activity (PKG and PKC signaling). Cardiomyocyte deletion of STIM1 in mice significantly reduced PKG and PKC signaling, along with calcineurin activity, resulting in lower heart rate and prolonged QT interval.
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