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Using a genetically targeted sensor to investigate the role of presenilin-1 in ER Ca2+ levels and dynamics.

ABSTRACT: The ER plays a fundamental role in storing cellular Ca(2+), generating Ca(2+) signals, and modulating Ca(2+) in both the cytosol and mitochondria. Genetically encoded Ca(2+) sensors can be explicitly targeted to the ER to directly define Ca(2+) levels and monitor fluxes of Ca(2+) within this organelle. In this study we use an ER-targeted Ca(2+) sensor to define both the level and dynamics of ER Ca(2+) in cells expressing mutant presenilin proteins. Growing evidence suggests the enigmatic presenilin-1 plays a role in regulating ER Ca(2+). Presenilin-1 was initially identified in a screen for genetic causes of inherited familial Alzheimer's disease (fAD). The connection between presenilin-1, calcium regulation, and Alzheimer's disease may provide the key to understanding the long-observed, but poorly understood, link between Alzheimer's disease and Ca(2+) dysregulation. In this study we examined seven fAD-causing mutations in presenilin-1 to define how they influence ER Ca(2+) levels and dynamics. We observed that some, but not all, mutations in PS1 decrease the level of Ca(2+) within the ER and this difference depends on the enzymatic activity of PS1. Two mutations tested altered the kinetics of Ca(2+) release from the ER upon ATP stimulation, resulting in faster spiking. Combined, these results indicate that mutations in PS1 can alter the balance of Ca(2+) in cells and have the potential to influence the nature of Ca(2+) signals.

SUBMITTER: McCombs JE

PROVIDER: S-EPMC3155245 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Using a genetically targeted sensor to investigate the role of presenilin-1 in ER Ca2+ levels and dynamics.

McCombs Janet E JE Gibson Emily A EA Palmer Amy E AE

Molecular bioSystems 20100408 9

The ER plays a fundamental role in storing cellular Ca(2+), generating Ca(2+) signals, and modulating Ca(2+) in both the cytosol and mitochondria. Genetically encoded Ca(2+) sensors can be explicitly targeted to the ER to directly define Ca(2+) levels and monitor fluxes of Ca(2+) within this organelle. In this study we use an ER-targeted Ca(2+) sensor to define both the level and dynamics of ER Ca(2+) in cells expressing mutant presenilin proteins. Growing evidence suggests the enigmatic preseni ...[more]

PMID: 20379593

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Project description:The endoplasmic reticulum/sarcoplasmic reticulum Ca2+ sensor stromal interaction molecule 1 (STIM1), a key mediator of store-operated Ca2+ entry, is expressed in cardiomyocytes and has been implicated in regulating multiple cardiac processes, including hypertrophic signaling. Interestingly, cardiomyocyte-restricted deletion of STIM1 (crSTIM1-KO) results in age-dependent endoplasmic reticulum stress, altered mitochondrial morphology, and dilated cardiomyopathy in mice. Here, we tested the hypothesis that STIM1 deficiency may also impact cardiac metabolism. Hearts isolated from 20-wk-old crSTIM1-KO mice exhibited a significant reduction in both oxidative and nonoxidative glucose utilization. Consistent with the reduction in glucose utilization, expression of glucose transporter 4 and AMP-activated protein kinase phosphorylation were all reduced, whereas pyruvate dehydrogenase kinase 4 and pyruvate dehydrogenase phosphorylation were increased, in crSTIM1-KO hearts. Despite similar rates of fatty acid oxidation in control and crSTIM1-KO hearts ex vivo, crSTIM1-KO hearts contained increased lipid/triglyceride content as well as increased fatty acid-binding protein 4, fatty acid synthase, acyl-CoA thioesterase 1, hormone-sensitive lipase, and adipose triglyceride lipase expression compared with control hearts, suggestive of a possible imbalance between fatty acid uptake and oxidation. Insulin-mediated alterations in AKT phosphorylation were observed in crSTIM1-KO hearts, consistent with cardiac insulin resistance. Interestingly, we observed abnormal mitochondria and increased lipid accumulation in 12-wk crSTIM1-KO hearts, suggesting that these changes may initiate the subsequent metabolic dysfunction. These results demonstrate, for the first time, that cardiomyocyte STIM1 may play a key role in regulating cardiac metabolism. NEW & NOTEWORTHY Little is known of the physiological role of stromal interaction molecule 1 (STIM1) in the heart. Here, we demonstrate, for the first time, that hearts lacking cardiomyocyte STIM1 exhibit dysregulation of both cardiac glucose and lipid metabolism. Consequently, these results suggest a potentially novel role for STIM1 in regulating cardiac metabolism.

Dataset Information

Using a genetically targeted sensor to investigate the role of presenilin-1 in ER Ca2+ levels and dynamics.

Publications

Using a genetically targeted sensor to investigate the role of presenilin-1 in ER Ca2+ levels and dynamics.

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