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Novel pyrazole compounds for pharmacological discrimination between receptor-operated and store-operated Ca2+ entry pathways
Article first published online: 29 NOV 2012
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Cannabinoids 2012. Guest Editor: Stephen PH Alexander
Volume 167, Issue 8, pages 1712–1722, December 2012
How to Cite
Schleifer, H., Doleschal, B., Lichtenegger, M., Oppenrieder, R., Derler, I., Frischauf, I., Glasnov, T., Kappe, C., Romanin, C. and Groschner, K. (2012), Novel pyrazole compounds for pharmacological discrimination between receptor-operated and store-operated Ca2+ entry pathways. British Journal of Pharmacology, 167: 1712–1722. doi: 10.1111/j.1476-5381.2012.02126.x
- Issue published online: 29 NOV 2012
- Article first published online: 29 NOV 2012
- Accepted manuscript online: 3 AUG 2012 07:20AM EST
- Manuscript Accepted: 11 JUL 2012
- Manuscript Revised: 4 JUL 2012
- Manuscript Received: 31 JAN 2012
- FWF (Austrian research fund). Grant Numbers: P21925-B19, P22565-B18
- DK+ Metabolic and Cardiovascular Disease. Grant Number: W1226-B18
Figure S1 Pyr3 acutely blocks a reconstituted CRAC pore in a dose-dependent, non-reversible manner as well as affecting sodium influx through it. (A) Time course of measured currents (n = 4 cells) of acute Pyr3 inhibition of CRAC in a HEK293 cell system expressing STIM1 and Orai1 to reconstitute the CRAC pore. (B) Time course of acute Pyr3 inhibition (3μM) in native RBL-2H3 cells (n = 6 cells). (C) Time course of currents (n = 8 cells) with acute Pyr3 inhibition of a reconstituted CRAC pore. Pyrazole compound was applied for only a limited time to examine reversibility of inhibitory effect. (D) Time course of Pyr3-effect (10 μM) on divalent-free sodium current through CRAC-pore after activation of current in Ca2+ containing buffer (n = 4 cells). All values are mean values ± SEM.
Figure S2 Pyr10 potently blocks DAG-mediated TRPC3 membrane currents. Mean values of OAG-induced (100 μM) TRPC3 currents in HEK293 cells in the absence and presence of 3 μM Pyr10. Mean values ± SEM of (n = 6).
Figure S3 Selectivity of Pyr10 and Pyr6 on TRPCs. Average inhibition of peak calcium entry level measured by Fura 2 Ca2+ imaging at 10 μM Pyr6 or Pyr10 in HEK293 cells overexpressing TRPC4beta-YFP, YFP-TRPC5 or GFP-TRPC6. HEK293 cells were challenged with carbachol (100 μM) to stimulate calcium entry and pre-incubated for 5 min with corresponding pyrazole compounds. Values are presented as percentage of non-inhibited carbachol-stimulated cells from the same experiments and were derived from a total of 27–55 cells from three individual experiments.
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