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Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs.
Cell Calcium. 2014 Dec; 56(6):482-92.CC

Abstract

The coupling of ER Ca(2+)-sensing STIM proteins and PM Orai Ca(2+) entry channels generates "store-operated" Ca(2+) signals crucial in controlling responses in many cell types. The dimeric derivative of 2-aminoethoxydiphenyl borinate (2-APB), DPB162-AE, blocks functional coupling between STIM1 and Orai1 with an IC50 (200 nM) 100-fold lower than 2-APB. Unlike 2-APB, DPB162-AE does not affect L-type or TRPC channels or Ca(2+) pumps at maximal STIM1-Orai1 blocking levels. DPB162-AE blocks STIM1-induced Orai1 or Orai2, but does not block Orai3 or STIM2-mediated effects. We narrowed the DPB162-AE site of action to the STIM-Orai activating region (SOAR) of STIM1. DPB162-AE does not prevent the SOAR-Orai1 interaction but potently blocks SOAR-mediated Orai1 channel activation, yet its action is not as an Orai1 channel pore blocker. Using the SOAR-F394H mutant which prevents both physical and functional coupling to Orai1, we reveal DPB162-AE rapidly restores SOAR-Orai binding but only slowly restores Orai1 channel-mediated Ca(2+) entry. With the same SOAR mutant, 2-APB induces rapid physical and functional coupling to Orai1, but channel activation is transient. We infer that the actions of both 2-APB and DPB162-AE are directed toward the STIM1-Orai1 coupling interface. Compared to 2-APB, DPB162-AE is a much more potent and specific STIM1/Orai1 functional uncoupler. DPB162-AE provides an important pharmacological tool and a useful mechanistic probe for the function and coupling between STIM1 and Orai1 channels.

Authors+Show Affiliations

Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, United States.Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, United States; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.Department of Physiology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Saitama 351-0198, Japan.Laboratory for Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.Laboratory for Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.Beijing Key Laboratory of Gene Resources and Molecular Development College of Life Sciences, Beijing Normal University, Beijing 100875, PR China. Electronic address: wyoujun@bnu.edu.cn.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States. Electronic address: dongill@psu.edu.

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25459299

Citation

Hendron, Eunan, et al. "Potent Functional Uncoupling Between STIM1 and Orai1 By Dimeric 2-aminodiphenyl Borinate Analogs." Cell Calcium, vol. 56, no. 6, 2014, pp. 482-92.
Hendron E, Wang X, Zhou Y, et al. Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs. Cell Calcium. 2014;56(6):482-92.
Hendron, E., Wang, X., Zhou, Y., Cai, X., Goto, J., Mikoshiba, K., Baba, Y., Kurosaki, T., Wang, Y., & Gill, D. L. (2014). Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs. Cell Calcium, 56(6), 482-92. https://doi.org/10.1016/j.ceca.2014.10.005
Hendron E, et al. Potent Functional Uncoupling Between STIM1 and Orai1 By Dimeric 2-aminodiphenyl Borinate Analogs. Cell Calcium. 2014;56(6):482-92. PubMed PMID: 25459299.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs. AU - Hendron,Eunan, AU - Wang,Xizhuo, AU - Zhou,Yandong, AU - Cai,Xiangyu, AU - Goto,Jun-ichi, AU - Mikoshiba,Katsuhiko, AU - Baba,Yoshihiro, AU - Kurosaki,Tomohiro, AU - Wang,Youjun, AU - Gill,Donald L, Y1 - 2014/10/23/ PY - 2014/09/10/received PY - 2014/10/10/revised PY - 2014/10/14/accepted PY - 2014/12/3/entrez PY - 2014/12/3/pubmed PY - 2015/8/5/medline KW - 2-APB KW - Calcium KW - Orai1 KW - Orai2 KW - Orai3 KW - STIM1 KW - STIM2 SP - 482 EP - 92 JF - Cell calcium JO - Cell Calcium VL - 56 IS - 6 N2 - The coupling of ER Ca(2+)-sensing STIM proteins and PM Orai Ca(2+) entry channels generates "store-operated" Ca(2+) signals crucial in controlling responses in many cell types. The dimeric derivative of 2-aminoethoxydiphenyl borinate (2-APB), DPB162-AE, blocks functional coupling between STIM1 and Orai1 with an IC50 (200 nM) 100-fold lower than 2-APB. Unlike 2-APB, DPB162-AE does not affect L-type or TRPC channels or Ca(2+) pumps at maximal STIM1-Orai1 blocking levels. DPB162-AE blocks STIM1-induced Orai1 or Orai2, but does not block Orai3 or STIM2-mediated effects. We narrowed the DPB162-AE site of action to the STIM-Orai activating region (SOAR) of STIM1. DPB162-AE does not prevent the SOAR-Orai1 interaction but potently blocks SOAR-mediated Orai1 channel activation, yet its action is not as an Orai1 channel pore blocker. Using the SOAR-F394H mutant which prevents both physical and functional coupling to Orai1, we reveal DPB162-AE rapidly restores SOAR-Orai binding but only slowly restores Orai1 channel-mediated Ca(2+) entry. With the same SOAR mutant, 2-APB induces rapid physical and functional coupling to Orai1, but channel activation is transient. We infer that the actions of both 2-APB and DPB162-AE are directed toward the STIM1-Orai1 coupling interface. Compared to 2-APB, DPB162-AE is a much more potent and specific STIM1/Orai1 functional uncoupler. DPB162-AE provides an important pharmacological tool and a useful mechanistic probe for the function and coupling between STIM1 and Orai1 channels. SN - 1532-1991 UR - https://www.unboundmedicine.com/medline/citation/25459299/Potent_functional_uncoupling_between_STIM1_and_Orai1_by_dimeric_2_aminodiphenyl_borinate_analogs_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0143-4160(14)00160-2 DB - PRIME DP - Unbound Medicine ER -