Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery
Abstract
:1. Cytosolic and Stored Calcium
1.1. Mobilization of S/ER Calcium Stores
1.2. Store-Operated Calcium Entry
1.3. STIM1, Orai1 and Disease
1.4. Mitochondrial Calcium Uptake and SOCE Crosstalk
2. Mitochondrial Calcium Uniporter (MCU)
2.1. Essential Mitochondrial Calcium Uniporter Regulator (EMRE)
2.2. Mitochondrial Calcium Uptake (MICU) Proteins
2.3. Mitochondrial Calcium Uniporter Dominant Negative Beta (MCUb) Subunit
2.4. Mitochondrial Calcium Uniporter Regulator-1 (MCUR1)
2.5. MCU and Disease
3. Leucine Zipper EF-Hand Containing Transmembrane Protein-1 (LETM1)
LETM1 and Disease
4. Generating New Therapeutics and Diagnostics from Protein Structures
4.1. Store-Operated and Mitochondrial Ca2+ Entry Proteins as Drug Targets
4.2. Initiating Protein Structure-based Drug Discovery
4.3. Concluding Remarks
Author Contributions
Funding
Conflicts of Interest
References
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Surface Receptor or Channel | Extracellular Signal | Immediate Effect of Receptor Activation | Downstream S/ER Ca2+ Release Channel | References |
---|---|---|---|---|
GPCR (e.g., PAR1) | Protein and small molecule ligands (e.g., thrombin) | PLCβ activation | IP3R | [38,39,40,41,42] |
a Polymodal GPCR (e.g., M3R and PTHR1) | Protein and small molecule ligands (e.g., carbachol/PTH) | PLCβ and adenylyl cyclase activation | IP3R | [43,44,45] |
RTK (e.g., IGF-1R) | Protein ligands (e.g., IGF-1) | PLCγ activation | IP3R | [46,47,48] |
b BCR | IgM-binding antigens | PLCγ activation | IP3R | [49,50,51,52] |
b TCR | Antigen presenting cell (MHC) | PLCγ activation | IP3R | [16,17,53,54] |
Fc | Antigen-antibody complex | PLCγ activation | IP3R | [16,17,55,56] |
VGIC (e.g., L-type Ca2+ channel) | Membrane depolarization | Ca2+ influx from the extracellular space | RyR | [57,58,59,60,61] |
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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. https://doi.org/10.3390/ijms21103642
Noble M, Lin Q-T, Sirko C, Houpt JA, Novello MJ, Stathopulos PB. Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery. International Journal of Molecular Sciences. 2020; 21(10):3642. https://doi.org/10.3390/ijms21103642
Chicago/Turabian StyleNoble, Megan, Qi-Tong Lin, Christian Sirko, Jacob A. Houpt, Matthew J. Novello, and Peter B. Stathopulos. 2020. "Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery" International Journal of Molecular Sciences 21, no. 10: 3642. https://doi.org/10.3390/ijms21103642