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Open AccessReview

Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery

1
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6A5C1, Canada
2
Department of Medicine, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6A5C1, Canada
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(10), 3642; https://doi.org/10.3390/ijms21103642
Received: 13 April 2020 / Revised: 11 May 2020 / Accepted: 17 May 2020 / Published: 21 May 2020
(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease)
Calcium (Ca2+) 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 Ca2+, resulting in the propagation of Ca2+ signals through the activation of processes, such as store-operated Ca2+ entry (SOCE). SOCE provides a sustained Ca2+ entry into the cytosol; moreover, the uptake of SOCE-mediated Ca2+ by mitochondria can shape cytosolic Ca2+ 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 Ca2+ signaling pathways that are involved in mediating S/ER stored Ca2+ release, SOCE, and mitochondrial Ca2+ 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 Ca2+ signaling pathways. Finally, we describe a simple strategy that aimed at applying the protein structural data to initiating drug design. View Full-Text
Keywords: calcium signaling; store-operated calcium entry; stromal interaction molecule; Orai1; mitochondrial calcium uniporter; leucine-zipper EF-hand containing transmembrane protein-1; ryanodine receptor; inositol 1,4,5 trisphosphate receptor; protein structure; drug development calcium signaling; store-operated calcium entry; stromal interaction molecule; Orai1; mitochondrial calcium uniporter; leucine-zipper EF-hand containing transmembrane protein-1; ryanodine receptor; inositol 1,4,5 trisphosphate receptor; protein structure; drug development
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MDPI and ACS Style

Noble, M.; Lin, Q.-T.; Sirko, C.; Houpt, J.A.; Novello, M.J.; Stathopulos, P.B. Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery. Int. J. Mol. Sci. 2020, 21, 3642.

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