Structurally related Ca<sup>2+</sup>-release activated Ca<sup>2+</sup> channel inhibitors exhibit distinct extracellular and intracellular modes of action.

Overview

1. Department of Biophysics, Alanya Alaaddin Keykubat University, Alanya, Antalya, Turkey
2. Department of Pharmacology, University of Cambridge, Cambridge, UK
3. Department of Biophysics, Akdeniz University, Antalya, Turkey

Abstract

Ca2+-release activated Ca2+ (CRAC) channels, formed by stromal interaction molecule (STIM) and Orai proteins, mediate store-operated Ca2+ entry and are implicated in autoimmune diseases, acute pancreatitis and cancer. Some small molecule inhibitors of these channels such as BTP2, Pyr6, Synta66 and GSK-7975A, are widely used as experimental tools, yet their precise mechanisms of action remain incompletely understood. Using whole-cell patch-clamp electrophysiology in rat basophilic leukaemia (RBL-1) cells, we determined whether each of these inhibitors acts from the extracellular or intracellular side of the plasma membrane. We found that BTP2 and GSK-7975A could suppress CRAC currents only when applied extracellularly, whereas Pyr6 and Synta66 were equally effective from either side. Molecular docking and molecular dynamics simulations using a rat Orai1 channel model identified plausible extracellular binding sites for all four inhibitors and additional putative intracellular binding sites for Pyr6 and Synta66. These predicted sites are located near regions that are likely to influence pore geometry and channel gating. Our findings suggest that, despite considerable structural similarity, these popular CRAC channel inhibitors exhibit mechanistically distinct interactions with Orai1, with important implications for their use as research tools and for future CRAC channel drug discovery.

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Data

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• alphafold.ebi.ac.uk/entry/q5m848, at EMBL-EBI; found in the text, “Molecular modelling and docking”

Data accessibility

The data supporting the findings of this study are publicly available in the Zenodo repository [56].

Supplementary material is available online [57].

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 12 November 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 6 keywords, 2 funders, 57 references.

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This paper

Gökçe, Y., Zhu, Y., Mahzabeen, S., Ghoorahoo, J., Harper, M. T., Yaraş, N., & Rahman, T. (2026). Structurally related Ca<sup>2+</sup>-release activated Ca<sup>2+</sup> channel inhibitors exhibit distinct extracellular and intracellular modes of action. Royal Society open science, 13(11), 261544. https://doi.org/10.1098/rsos.261544

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