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Structural and Mechanistic Insights of CRAC Channel as a Drug Target in Autoimmune Disorder.
Curr Drug Targets. 2020; 21(1):55-75.CD

Abstract

BACKGROUND

Calcium (Ca2+) ion is a major intracellular signaling messenger, controlling a diverse array of cellular functions like gene expression, secretion, cell growth, proliferation, and apoptosis. The major mechanism controlling this Ca2+ homeostasis is store-operated Ca2+ release-activated Ca2+ (CRAC) channels. CRAC channels are integral membrane protein majorly constituted via two proteins, the stromal interaction molecule (STIM) and ORAI. Following Ca2+ depletion in the Endoplasmic reticulum (ER) store, STIM1 interacts with ORAI1 and leads to the opening of the CRAC channel gate and consequently allows the influx of Ca2+ ions. A plethora of studies report that aberrant CRAC channel activity due to Loss- or gain-of-function mutations in ORAI1 and STIM1 disturbs this Ca2+ homeostasis and causes several autoimmune disorders. Hence, it clearly indicates that the therapeutic target of CRAC channels provides the space for a new approach to treat autoimmune disorders.

OBJECTIVE

This review aims to provide the key structural and mechanical insights of STIM1, ORAI1 and other molecular modulators involved in CRAC channel regulation.

RESULTS AND CONCLUSION

Understanding the structure and function of the protein is the foremost step towards improving the effective target specificity by limiting their potential side effects. Herein, the review mainly focusses on the structural underpinnings of the CRAC channel gating mechanism along with its biophysical properties that would provide the solid foundation to aid the development of novel targeted drugs for an autoimmune disorder. Finally, the immune deficiencies caused due to mutations in CRAC channel and currently used pharmacological blockers with their limitation are briefly summarized.

Authors+Show Affiliations

Ion Channel Biology Laboratory, AU-KBC Research Centre, Madras Institute of Technology, Anna University, Chrompet, Chennai -600 044, India.Ion Channel Biology Laboratory, AU-KBC Research Centre, Madras Institute of Technology, Anna University, Chrompet, Chennai -600 044, India.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

31556856

Citation

Bhuvaneshwari, Sampath, and Kavitha Sankaranarayanan. "Structural and Mechanistic Insights of CRAC Channel as a Drug Target in Autoimmune Disorder." Current Drug Targets, vol. 21, no. 1, 2020, pp. 55-75.
Bhuvaneshwari S, Sankaranarayanan K. Structural and Mechanistic Insights of CRAC Channel as a Drug Target in Autoimmune Disorder. Curr Drug Targets. 2020;21(1):55-75.
Bhuvaneshwari, S., & Sankaranarayanan, K. (2020). Structural and Mechanistic Insights of CRAC Channel as a Drug Target in Autoimmune Disorder. Current Drug Targets, 21(1), 55-75. https://doi.org/10.2174/1389450120666190926150258
Bhuvaneshwari S, Sankaranarayanan K. Structural and Mechanistic Insights of CRAC Channel as a Drug Target in Autoimmune Disorder. Curr Drug Targets. 2020;21(1):55-75. PubMed PMID: 31556856.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural and Mechanistic Insights of CRAC Channel as a Drug Target in Autoimmune Disorder. AU - Bhuvaneshwari,Sampath, AU - Sankaranarayanan,Kavitha, PY - 2019/05/09/received PY - 2019/08/20/revised PY - 2019/08/20/accepted PY - 2019/9/27/pubmed PY - 2021/2/3/medline PY - 2019/9/27/entrez KW - Autoimmune disorder KW - CRAC channel KW - ORAI KW - SOCE KW - STIM KW - calcium. SP - 55 EP - 75 JF - Current drug targets JO - Curr Drug Targets VL - 21 IS - 1 N2 - BACKGROUND: Calcium (Ca2+) ion is a major intracellular signaling messenger, controlling a diverse array of cellular functions like gene expression, secretion, cell growth, proliferation, and apoptosis. The major mechanism controlling this Ca2+ homeostasis is store-operated Ca2+ release-activated Ca2+ (CRAC) channels. CRAC channels are integral membrane protein majorly constituted via two proteins, the stromal interaction molecule (STIM) and ORAI. Following Ca2+ depletion in the Endoplasmic reticulum (ER) store, STIM1 interacts with ORAI1 and leads to the opening of the CRAC channel gate and consequently allows the influx of Ca2+ ions. A plethora of studies report that aberrant CRAC channel activity due to Loss- or gain-of-function mutations in ORAI1 and STIM1 disturbs this Ca2+ homeostasis and causes several autoimmune disorders. Hence, it clearly indicates that the therapeutic target of CRAC channels provides the space for a new approach to treat autoimmune disorders. OBJECTIVE: This review aims to provide the key structural and mechanical insights of STIM1, ORAI1 and other molecular modulators involved in CRAC channel regulation. RESULTS AND CONCLUSION: Understanding the structure and function of the protein is the foremost step towards improving the effective target specificity by limiting their potential side effects. Herein, the review mainly focusses on the structural underpinnings of the CRAC channel gating mechanism along with its biophysical properties that would provide the solid foundation to aid the development of novel targeted drugs for an autoimmune disorder. Finally, the immune deficiencies caused due to mutations in CRAC channel and currently used pharmacological blockers with their limitation are briefly summarized. SN - 1873-5592 UR - https://www.unboundmedicine.com/medline/citation/31556856/Structural_and_Mechanistic_Insights_of_CRAC_Channel_as_a_Drug_Target_in_Autoimmune_Disorder_ L2 - http://www.eurekaselect.com/175152/article DB - PRIME DP - Unbound Medicine ER -