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Effects of Drugs with Muscle-Related Side Effects and Affinity for Calsequestrin on the Calcium Regulatory Function of Sarcoplasmic Reticulum Microsomes

Department of Chemistry (M.T., W.F.S., C.K.) and School of Molecular Biosciences (E.K., C.K.), Washington State University, Pullman, Washington

The tight regulation of Ca²⁺ release to and clearance from the cytosol is essential for normal excitation-contraction coupling in both skeletal and cardiac muscles. Calsequestrin (CSQ) is one of the major components in the sarcoplasmic reticulum (SR) of both skeletal and cardiac muscle. Previously, we showed that several pharmaceutical drugs, such as phenothiazine derivatives, tricyclic antidepressants, anthracycline derivatives, and other hydrophobic compounds bind CSQ with K_d values in the micromolar range and significantly reduce the Ca²⁺ binding capacity of cardiac CSQ (Mol Pharmacol 67:97–104, 2005). Because of its key role in Ca²⁺ regulation, this interference with CSQ function could well produce adverse physiological consequences and potentially be linked to the known muscle-related side effects of these drugs. To further understand the molecular mechanism of undesirable drug effects or adverse drug reactions among those compounds, we examined their effect on the SR microsome. The results clearly showed that these compounds affect Ca²⁺ release and reduce the total Ca²⁺ content of the purified SR microsomes, matching well with our previous results with purified recombinant CSQ. Liquid chromatography-mass spectrometry/mass spectrometry showed that the antipsychotic drug trifluoperazine penetrates well into the SR microsome as expected from the reported and calculated log S (aqueous solubility) and log P (partition coefficient) values among the phenothiazine derivatives. We therefore propose that a certain portion of the muscle-related (both cardiac and skeletal) complications of these drugs is caused by the altered Ca²⁺ regulation of the SR mediated by their adverse interaction with CSQ.

Address correspondence to: Dr. ChulHee Kang, Room 264, Fulmer Building, School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4660. E-mail: chkang{at}wsunix.wsu.edu