Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery
Calcium (Ca<sup>2+</sup>) is a universal signaling ion that is essential for the life and death processes of all eukaryotes. In humans, numerous cell stimulation pathways lead to the mobilization of sarco/endoplasmic reticulum (S/ER) stored Ca<sup>2+</sup>, resulting in the p...
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| Format: | Article |
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MDPI AG
2020-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/10/3642 |
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| author | Megan Noble Qi-Tong Lin Christian Sirko Jacob A. Houpt Matthew J. Novello Peter B. Stathopulos |
| author_facet | Megan Noble Qi-Tong Lin Christian Sirko Jacob A. Houpt Matthew J. Novello Peter B. Stathopulos |
| author_sort | Megan Noble |
| collection | DOAJ |
| description | Calcium (Ca<sup>2+</sup>) is a universal signaling ion that is essential for the life and death processes of all eukaryotes. In humans, numerous cell stimulation pathways lead to the mobilization of sarco/endoplasmic reticulum (S/ER) stored Ca<sup>2+</sup>, resulting in the propagation of Ca<sup>2+</sup> signals through the activation of processes, such as store-operated Ca<sup>2+</sup> entry (SOCE). SOCE provides a sustained Ca<sup>2+</sup> entry into the cytosol; moreover, the uptake of SOCE-mediated Ca<sup>2+</sup> by mitochondria can shape cytosolic Ca<sup>2+</sup> signals, function as a feedback signal for the SOCE molecular machinery, and drive numerous mitochondrial processes, including adenosine triphosphate (ATP) production and distinct cell death pathways. In recent years, tremendous progress has been made in identifying the proteins mediating these signaling pathways and elucidating molecular structures, invaluable for understanding the underlying mechanisms of function. Nevertheless, there remains a disconnect between using this accumulating protein structural knowledge and the design of new research tools and therapies. In this review, we provide an overview of the Ca<sup>2+</sup> signaling pathways that are involved in mediating S/ER stored Ca<sup>2+</sup> release, SOCE, and mitochondrial Ca<sup>2+</sup> uptake, as well as pinpoint multiple levels of crosstalk between these pathways. Further, we highlight the significant protein structures elucidated in recent years controlling these Ca<sup>2+</sup> signaling pathways. Finally, we describe a simple strategy that aimed at applying the protein structural data to initiating drug design. |
| first_indexed | 2024-03-10T19:41:08Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T19:41:08Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ed89a9a083c645529c6d916ad3e7e2802023-11-20T01:14:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-05-012110364210.3390/ijms21103642Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug DiscoveryMegan Noble0Qi-Tong Lin1Christian Sirko2Jacob A. Houpt3Matthew J. Novello4Peter B. Stathopulos5Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6A5C1, CanadaDepartment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6A5C1, CanadaDepartment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6A5C1, CanadaDepartment of Medicine, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6A5C1, CanadaDepartment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6A5C1, CanadaDepartment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6A5C1, CanadaCalcium (Ca<sup>2+</sup>) is a universal signaling ion that is essential for the life and death processes of all eukaryotes. In humans, numerous cell stimulation pathways lead to the mobilization of sarco/endoplasmic reticulum (S/ER) stored Ca<sup>2+</sup>, resulting in the propagation of Ca<sup>2+</sup> signals through the activation of processes, such as store-operated Ca<sup>2+</sup> entry (SOCE). SOCE provides a sustained Ca<sup>2+</sup> entry into the cytosol; moreover, the uptake of SOCE-mediated Ca<sup>2+</sup> by mitochondria can shape cytosolic Ca<sup>2+</sup> signals, function as a feedback signal for the SOCE molecular machinery, and drive numerous mitochondrial processes, including adenosine triphosphate (ATP) production and distinct cell death pathways. In recent years, tremendous progress has been made in identifying the proteins mediating these signaling pathways and elucidating molecular structures, invaluable for understanding the underlying mechanisms of function. Nevertheless, there remains a disconnect between using this accumulating protein structural knowledge and the design of new research tools and therapies. In this review, we provide an overview of the Ca<sup>2+</sup> signaling pathways that are involved in mediating S/ER stored Ca<sup>2+</sup> release, SOCE, and mitochondrial Ca<sup>2+</sup> uptake, as well as pinpoint multiple levels of crosstalk between these pathways. Further, we highlight the significant protein structures elucidated in recent years controlling these Ca<sup>2+</sup> signaling pathways. Finally, we describe a simple strategy that aimed at applying the protein structural data to initiating drug design.https://www.mdpi.com/1422-0067/21/10/3642calcium signalingstore-operated calcium entrystromal interaction moleculeOrai1mitochondrial calcium uniporterleucine-zipper EF-hand containing transmembrane protein-1 |
| spellingShingle | Megan Noble Qi-Tong Lin Christian Sirko Jacob A. Houpt Matthew J. Novello Peter B. Stathopulos Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery International Journal of Molecular Sciences calcium signaling store-operated calcium entry stromal interaction molecule Orai1 mitochondrial calcium uniporter leucine-zipper EF-hand containing transmembrane protein-1 |
| title | Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery |
| title_full | Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery |
| title_fullStr | Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery |
| title_full_unstemmed | Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery |
| title_short | Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery |
| title_sort | structural mechanisms of store operated and mitochondrial calcium regulation initiation points for drug discovery |
| topic | calcium signaling store-operated calcium entry stromal interaction molecule Orai1 mitochondrial calcium uniporter leucine-zipper EF-hand containing transmembrane protein-1 |
| url | https://www.mdpi.com/1422-0067/21/10/3642 |
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