Commonly used Ryanodine receptor activator, 4-chloro-m-cresol (4CmC) is also an activator of SERCA Ca2+ pumps

4-Chloro-m-cresol (4CmC) is an extensively used activator of ryanodine receptors (RyRs). Studies have shown that 4CmC, at a concentration of 1 mM, is sufficient to cause Ca(2+) release through RyRs. Here, we show that mM concentrations of 4CmC also inhibit the sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase (SERCA), (IC(50) 2-3mM) and cause Ca(2+) release. 4CmC also causes increased intracellular [Ca(2+)] levels in COS-7 cells, which lack functional RyRs. Thus, any increase in [Ca(2+)] levels associated with use of 4CmC (>or= 1mM) could lead to non-specific Ca(2+) changes due to SERCA inhibition rather than RyR activation.