TY - JOUR T1 - Effects of Drugs with Muscle-Related Side Effects and Affinity for Calsequestrin on the Calcium Regulatory Function of Sarcoplasmic Reticulum Microsomes JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1708 LP - 1715 DO - 10.1124/mol.105.016253 VL - 68 IS - 6 AU - EunJung Kim AU - Maggie Tam AU - William F. Siems AU - ChulHee Kang Y1 - 2005/12/01 UR - http://molpharm.aspetjournals.org/content/68/6/1708.abstract N2 - 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 Kd 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. ER -