Effects of drugs with muscle-related side effects and affinity for calsequestrin on the calcium regulatory function of sarcoplasmic reticulum microsomes
Effects of drugs with muscle-related side effects and affinity for calsequestrin on the calcium regulatory function of sarcoplasmic reticulum microsomes
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DOI：
10.1124/mol.105.016253
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发表时间：
2005-12-01
影响因子：
3.6
通讯作者：
Kang, CH
中科院分区：
文献类型：
--
作者：
Kim, E;Tam, M;Kang, CH
Ca 2+释放到胞质溶胶和从胞质溶胶清除的严格调节对于骨骼肌和心肌中的正常兴奋-收缩偶联是必不可少的。钙螯合蛋白（CSQ）是骨骼肌和心肌肌浆网（SR）的主要成分之一。以前，我们表明，几种药物，如吩噻嗪衍生物，三环类抗抑郁药，蒽环类衍生物，和其他疏水化合物结合CSQ的Kd值在微摩尔范围内，并显着降低心脏CSQ的Ca 2+结合能力（分子药理学67：97 - 104，2005）。由于其在Ca 2+调节中的关键作用，这种对CSQ功能的干扰很可能产生不良生理后果，并可能与这些药物的已知肌肉相关副作用有关。为了进一步了解这些化合物的不良药物作用或药物不良反应的分子机制，我们研究了它们对SR微粒体的影响。结果清楚地表明，这些化合物影响Ca 2+释放，并降低纯化的SR微粒体的总Ca 2+含量，与我们以前用纯化的重组CSQ的结果匹配良好。液相色谱-质谱/质谱表明，抗精神病药物三氟拉嗪渗透到SR微粒体中，正如所预期的，从报告和计算的log S（水溶性）和log P（分配系数）值之间的吩噻嗪衍生物。因此，我们提出，这些药物的肌肉相关（心脏和骨骼）并发症的一部分是由改变钙调节SR介导的CSQ的不利相互作用。
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.