In this study we performed the comprehensive pharmacological analysis of two stereoisomers of 4-chloro-meta-cresol (4CMC), a popular ryanodine receptor (RyR) agonist used in muscle research. Experiments investigating the Ca-releasing action of the isomers demonstrated that the most potent isomer was 4-chloro-orto-cresol (4COC) (EC = 55 ± 14 μM), although 3-chloro-para-cresol (3CPC) was more effective, as it was able to induce higher magnitude of Ca flux from isolated terminal cisterna vesicles. Nevertheless, 3CPC stimulated the hydrolytic activity of the sarcoplasmic reticulum ATP-ase (SERCA) with an EC of 91 ± 17 μM, while 4COC affected SERCA only in the millimolar range (IC = 1370 ± 88 μM). IC of 4CMC for SERCA pump was 167 ± 8 μM, indicating that 4CMC is not a specific RyR agonist either, as it activated RyR in a similar concentration (EC = 121 ± 20 μM). Our data suggest that the use of 4COC might be more beneficial than 4CMC in experiments, when Ca release should be triggered through RyRs without influencing SERCA activity.
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