Potential role of cardiac calsequestrin in the lethal arrhythmic effects of cocaine.
Potential role of cardiac calsequestrin in the lethal arrhythmic effects of cocaine.
复制标题
DOI：
10.1016/j.drugalcdep.2013.06.012
复制
发表时间：
2013-12-01
影响因子：
4.2
通讯作者：
Kang C
中科院分区：
文献类型：
--
作者：
Sanchez EJ;Hayes RP;Barr JT;Lewis KM;Webb BN;Subramanian AK;Nissen MS;Jones JP;Shelden EA;Sorg BA;Fill M;Schenk JO;Kang C
可卡因相关的死亡人数不断上升，过量服用通常会导致致命的心脏毒性作用。我们的方法并行采用等温滴定量热法 (ITC) 和光散射，证实了人心脏钙螯合蛋白 (CASQ2) 对可卡因的显着亲和力。 Calsequestrin (CASQ) 是心肌和骨骼肌肌浆网 (SR) 内的主要 Ca2+ 储存蛋白。 CASQ 通过其独特的 Ca2+ 依赖性寡聚作用充当 Ca2+ 缓冲剂和 Ca2+ 通道调节剂。平衡透析和原子吸收光谱实验说明了可卡因对 CASQ2 聚合的微扰效应，导致其 Ca2+ 结合能力大幅降低。我们还证实了可卡因在大鼠心脏组织中的积累以及可卡因对培养的 C2C12 细胞的实质性影响。使用甲基苯丙胺作为对照进行了相同的实验，其既没有表现出对 CASQ2 的亲和力，也没有对其功能产生任何显着影响。从我们的单通道记录来看，可卡因对 Ca2+ 释放通道没有任何直接影响，因此这些研究为可卡因如何干扰正常的 E-C 耦合机制并导致致命的心律失常后果提供了新的见解。我们认为可卡因通过其对 CASQ2 的亲和力在 SR 中积累，并通过改变正常的 CASQ2 Ca2+ 依赖性聚合来影响 SR Ca2+ 储存和释放。通过这种机制，使用可卡因可能会产生严重的心脏问题，特别是对于 CASQ2 基因受损、其他 E-C 耦合成分缺陷或可卡因代谢和清除受损的人。
Cocaine-related deaths are continuously rising and its overdose is often associated with lethal cardiotoxic effects. Our approach, employing isothermal titration calorimetry (ITC) and light scattering in parallel, has confirmed the significant affinity of human cardiac calsequestrin (CASQ2) for cocaine. Calsequestrin (CASQ) is a major Ca2+-storage protein within the sarcoplasmic reticulum (SR) of both cardiac and skeletal muscles. CASQ acts as a Ca2+ buffer and Ca2+-channel regulator through its unique Ca2+-dependent oligomerization. Equilibrium dialysis and atomic absorption spectroscopy experiments illustrated the perturbational effect of cocaine on CASQ2 polymerization, resulting in substantial reduction of its Ca2+-binding capacity. We also confirmed the accumulation of cocaine in rat heart tissue and the substantial effects cocaine has on cultured C2C12 cells. The same experiments were performed with methamphetamine as a control, which displayed neither affinity for CASQ2 nor any significant effects on its function. Since cocaine did not have any direct effect on the Ca2+-release channel judging from our single channel recordings, these studies provide new insights into how cocaine may interfere with the normal E-C coupling mechanism with lethal arrhythmogenic consequences. We propose that cocaine accumulates in SR through its affinity for CASQ2 and affects both SR Ca2+ storage and release by altering the normal CASQ2 Ca2+-dependent polymerization. By this mechanism, cocaine use could produce serious cardiac problems, especially in people who have genetically-impaired CASQ2, defects in other E-C coupling components, or compromised cocaine metabolism and clearance.
登录
查看更多内容
影响因子：
3.6
作者：
Kim, E;Tam, M;Kang, CH
通讯作者：
Kang, CH
影响因子：
4
作者：
Cho, Jeong Hoon;Ko, Kyung Min;Ahnn, Joohong
通讯作者：
Ahnn, Joohong
DOI：
10.1152/ajpheart.01187.2006
发表时间：
2007-07-01
影响因子：
4.8
作者：
Gergs, Ulrich;Berndt, Tobias;Neumann, Joachim
通讯作者：
Neumann, Joachim
影响因子：
2.9
作者：
BAUMAN, JL;GRAWE, JJ;HARIMAN, RJ
通讯作者：
HARIMAN, RJ
影响因子：
4.7
作者：
Browning JR;Browning DA;Maxwell AO;Dong Y;Jansen HT;Panksepp J;Sorg BA
通讯作者：
Sorg BA