Commonly used ryanodine receptor activator, 4-chloro-m-cresol (4CmC), is also an inhibitor 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 Ca2+ release through RyRs. Here, we show that mM concentrations of 4CmC also inhibit the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA), (IC50 2–3mM) and cause Ca2+ release. 4CmC also causes increased intracellular [Ca2+] levels in COS-7 cells, which lack functional RyRs. Thus, any increase in [Ca2+] levels associated with use of 4CmC (≥ 1mM) could lead to non-specific Ca2+ changes due to SERCA inhibition rather than RyR activation.