The Ca2+ current passing through the plasma membrane is known as the Ca2+ release-activated Ca2+ (CRAC) current, and it is believed to play a central role in many physiological processes such as gene transcription, proliferation, and cytokine release. GSK-7975A is a potent and orally available CRAC channel blocker with an IC50 of 0.34 μM. GSK-7975A (1 μM) reduced FcεRI-dependent Ca2+ influx and 3 μM of it reduced the release of histamine, leukotriene C4, and cytokines (IL-5/-8/-13 and TNFα) by up to 50%[4]. GSK-7975A separately inhibited toxin-induced activation of ORAI1 and/or activation of Ca2+ currents after Ca2+ release, in a concentration-dependent manner, in mouse and human pancreatic acinar cells. In 3 clinically representative mouse models of acute pancreatitis, GSK-7975A inhibited all local and systemic features of acute pancreatitis in all 3 models, in dose- and time-dependent manners[5].
GSK-7975A 细胞实验
Cell Line
Concentration
Treated Time
Description
References
human lung mast cells (HLMCs)
1 μM
To assess whether Ca2+ influx through Orai channels contributes to KCa3.1 opening, the selective Orai channel blocker GSK-7975A was used. KCa3.1 currents elicited in response to FcεRI-dependent HLMC activation were significantly attenuated with the subsequent addition of 1 μM GSK-7975A.
Cell Commun Signal. 2015 Jul 16;13:32
human coronary artery endothelial cells (hCAECs)
10 µmol/L
2 minutes
Inhibited thapsigargin-induced Ca2+ influx, indicating that Ca2+ entry is mediated by SOCE and Orai channels.
GSK-7975A markedly reduced asparaginase-induced Ca2+ entry and also protected effectively against the development of necrosis.
Philos Trans R Soc Lond B Biol Sci. 2016 Aug 5;371(1700):20150423
SU-DHL-4 cells
3 µM
30 minutes
GSK-7975A selectively inhibits SOCE without affecting ER Ca2+ content or SERCA2b ATPase activity, and does not reduce BIRD-2-induced apoptosis.
Cell Death Discov. 2018 Nov 2;4:101
human primary myoblasts
10 μM
GSK-7975A inhibited constitutive Ca2+ entry in myoblasts expressing ORAI1-T184M and -V107M.
J Physiol. 2019 Jan;597(2):561-582
HEK-293T cells
10 μM
GSK-7975A efficiently blocked the basal Mn2+ 'leak' and SOCE mediated by TAM-associated ORAI1 mutants (V107M and T184M).
J Physiol. 2019 Jan;597(2):561-582
mouse urethral smooth muscle cells (USMCs)
1 μM
GSK-7975A reduced the frequency, amplitude, and spatial spread of Ca2+ waves in USMCs, indicating the importance of Orai channels in maintaining Ca2+ waves.
J Physiol. 2018 Apr 15;596(8):1433-1466
E13 cortical neurons
5 μM
Applied from time +60 s and remained present till the end of the recording
GSK-7975A reduced the peak amplitude of SOCE by ~50%
Front Pharmacol. 2016 Dec 12;7:486
human umbilical vein endothelial cells (HUVEC)
70 μM
24 hours
To evaluate the effect of GSK-7975A on HUVEC migration, results showed that GSK-7975A significantly inhibited cell migration.
Front Cell Dev Biol. 2021 Mar 4;9:639952
human umbilical vein endothelial cells (HUVEC)
50 and 70 μM
18 hours
To evaluate the effect of GSK-7975A on HUVEC tube formation, results showed that GSK-7975A significantly reduced the formation of tube-like structures.
Front Cell Dev Biol. 2021 Mar 4;9:639952
airway smooth muscle cells (ASMCs)
1 μM to 100 μM
5 minutes to 10 minutes
To evaluate the effect of GSK-7975A on IP3 receptor activation, results showed that GSK-7975A did not affect IP3-induced calcium signaling.
J Physiol. 2017 May 15;595(10):3203-3218
GSK-7975A 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice (SV129)
Retinal angiogenesis model
Intraperitoneal injection
2.6, 4.0, 7.9, 15.9, and 31.8 mg/kg
Injected at postnatal days P3, P4, and P5, and analyzed at P6
To evaluate the effect of GSK-7975A on retinal angiogenesis, results showed that GSK-7975A significantly reduced vessel length and the number of junctions, while increasing lacunarity.
Front Cell Dev Biol. 2021 Mar 4;9:639952
Mice
Precision-cut lung slices (PCLS)
Perfusion
1 μM to 100 μM
Continuous exposure for 5 to 10 minutes
To evaluate the effect of GSK-7975A on airway contraction and calcium oscillations, results showed that GSK-7975A could fully relax airway contraction and stop calcium oscillations.
J Physiol. 2017 May 15;595(10):3203-3218
Mouse
Mouse urethral smooth muscle
In vitro perfusion
1 μM
GSK-7975A reduced urethral contractions induced by phenylephrine, suggesting that Orai channels function effectively as receptor-operated channels.
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