Dataset Information

Orai, STIM, and PMCA contribute to reduced calcium signal generation in CD8⁺ T cells of elderly mice.

ABSTRACT: Ca²⁺ is a crucial second messenger for proper T cell function. Considering the relevance of Ca²⁺ signals for T cell functionality it is surprising that no mechanistic insights into T cell Ca²⁺ signals from elderly individuals are reported. The main Ca²⁺ entry mechanism in T cells are STIM-activated Orai channels. Their role during lymphocyte aging is completely unknown. Here, we report not only reduced Ca²⁺ signals in untouched and stimulated, but also in central and effector memory CD8⁺ T cells from elderly (18-24 months) compared to adult (3-6 months) mice. Two mechanisms contribute to the overall reduction in Ca²⁺ signals of CD8⁺ T cells of elderly mice: 1) Reduced Ca²⁺ currents through Orai channels due to decreased expressions of STIMs and Orais. 2) A faster extrusion of Ca²⁺ owing to an increased expression of PMCA4. The reduced Ca²⁺ signals correlated with a resistance of the cytotoxic efficiency of CD8⁺ T cells to varying free [Ca²⁺]_ext with age. In summary, reduced STIM/Orai expression and increased Ca²⁺ clearing rates following enhanced PMCA4 expression contribute to reduced Ca²⁺ signals in CD8⁺ T cells of elderly mice. These changes are apparently relevant to immune function as they reduce the Ca²⁺ dependency of CTL cytotoxicity.

SUBMITTER: Angenendt A

PROVIDER: S-EPMC7066920 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Orai, STIM, and PMCA contribute to reduced calcium signal generation in CD8+ T cells of elderly mice.

Angenendt Adrian A Steiner Romy R Knörck Arne A Schwär Gertrud G Konrad Maik M Krause Elmar E Lis Annette A

Aging 20200212 4

Ca2+ is a crucial second messenger for proper T cell function. Considering the relevance of Ca2+ signals for T cell functionality it is surprising that no mechanistic insights into T cell Ca2+ signals from elderly individuals are reported. The main Ca2+ entry mechanism in T cells are STIM-activated Orai channels. Their role during lymphocyte aging is completely unknown. Here, we report not only reduced Ca2+ signals in untouched and stimulate ...[more]

PMID: 32062611

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Project description:Tight spatiotemporal regulation of intracellular Ca2+ plays a critical role in regulating diverse cellular functions including cell survival, metabolism, and transcription. As a result, eukaryotic cells have developed a wide variety of mechanisms for controlling Ca2+ influx and efflux across the plasma membrane as well as Ca2+ release and uptake from intracellular stores. The STIM and Orai protein families comprising of STIM1, STIM2, Orai1, Orai2, and Orai3, are evolutionarily highly conserved proteins that are core components of all mammalian Ca2+ signaling systems. STIM1 and Orai1 are considered key players in the regulation of Store Operated Calcium Entry (SOCE), where release of Ca2+ from intracellular stores such as the Endoplasmic/Sarcoplasmic reticulum (ER/SR) triggers Ca2+ influx across the plasma membrane. SOCE, which has been widely characterized in non-excitable cells, plays a central role in Ca2+-dependent transcriptional regulation. In addition to their role in Ca2+ signaling, STIM1 and Orai1 have been shown to contribute to the regulation of metabolism and mitochondrial function. STIM and Orai proteins are also subject to redox modifications, which influence their activities. Considering their ubiquitous expression, there has been increasing interest in the roles of STIM and Orai proteins in excitable cells such as neurons and myocytes. While controversy remains as to the importance of SOCE in excitable cells, STIM1 and Orai1 are essential for cellular homeostasis and their disruption is linked to various diseases associated with aging such as cardiovascular disease and neurodegeneration. The recent identification of splice variants for most STIM and Orai isoforms while complicating our understanding of their function, may also provide insight into some of the current contradictions on their roles. Therefore, the goal of this review is to describe our current understanding of the molecular regulation of STIM and Orai proteins and their roles in normal physiology and diseases of aging, with a particular focus on heart disease and neurodegeneration.

Dataset Information

Orai, STIM, and PMCA contribute to reduced calcium signal generation in CD8⁺ T cells of elderly mice.

Publications

Orai, STIM, and PMCA contribute to reduced calcium signal generation in CD8<sup>+</sup> T cells of elderly mice.

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