Development of chemical tools based on GSK-7975A to study store-operated calcium entry in cells.

Tscherrig, Dominic; Bhardwaj, Rajesh; Biner, Daniel; Dernič, Jan; Ross-Kaschitza, Daniela; Peinelt, Christine; Hediger, Matthias A; Lochner, Martin (2024). Development of chemical tools based on GSK-7975A to study store-operated calcium entry in cells. Cell calcium, 117, p. 102834. Elsevier 10.1016/j.ceca.2023.102834

1-s2.0-S0143416023001458-main.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (6MB) | Preview

Many physiological functions, such as cell differentiation, proliferation, muscle contraction, neurotransmission and fertilisation, are regulated by changes of Ca2+ levels. The major Ca2+ store in cells is the endoplasmic reticulum (ER). Certain cellular processes induce ER store depletion, e.g. by activating IP3 receptors, that in turn induces a store refilling process known as store-operated calcium entry (SOCE). This refilling process entails protein-protein interactions between Ca2+ sensing stromal interaction molecules (STIM) in the ER membrane and Orai proteins in the plasma membrane. Fully assembled STIM/Orai complexes then form highly selective Ca2+ channels called Ca2+ release-activated Ca2+ Channels (CRAC) through which Ca2+ ions flow into the cytosol and subsequently are pumped into the ER by the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). Abnormal SOCE has been associated with numerous human diseases and cancers, and therefore key players STIM and Orai have attracted significant therapeutic interest. Several potent experimental and clinical candidate compounds have been developed and have helped to study SOCE in various cell types. We have synthesized multiple novel small-molecule probes based on the known SOCE inhibitor GSK-7975A. Here we present GSK-7975A derivatives, which feature photo-caging, photo-crosslinking, biotin and clickable moieties, and also contain deuterium labels. Evaluation of these GSK-7975A probes using a fluorometric imaging plate reader (FLIPR)-Tetra-based Ca2+ imaging assay showed that most synthetic modifications did not have a detrimental impact on the SOCE inhibitory activity. The photo-caged GSK-7975A was also used in patch-clamp electrophysiology experiments. In summary, we have developed a number of active, GSK-7975A-based molecular probes that have interesting properties and therefore are useful experimental tools to study SOCE in various cells and settings.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie

UniBE Contributor:

Tscherrig, Dominic Armin, Bhardwaj, Rajesh, Biner, Daniel, Dernič, Jan, Ross, Daniela, Peinelt, Christine, Hediger, Matthias, Lochner, Martin


500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
500 Science > 540 Chemistry








Pubmed Import

Date Deposited:

28 Nov 2023 14:23

Last Modified:

16 Jan 2024 00:15

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Calcium imaging assay Patch-clamp electrophysiology Photo-affinity labelling Photo-caged compound Store-operated calcium entry Synthetic molecular probe




Actions (login required)

Edit item Edit item
Provide Feedback