AMP is a partial agonist at the sheep cardiac ryanodine receptor
AMP is a partial agonist at the sheep cardiac ryanodine receptor
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DOI：
10.1038/sj.bjp.0702491
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发表时间：
1999-05-01
影响因子：
7.3
通讯作者：
Sitsapesan, R
中科院分区：
文献类型：
--
作者：
Ching, LL;Williams, AJ;Sitsapesan, R
我们已经研究了AMP在各种细胞质[Ca2+]中调节天然绵羊心脏ryanodine受体（RyR）通道的能力。在平面磷脂双分子层中加入通道，并在电压阻尼条件下监测通过双分子层的电流波动我们证明，AMP只有在细胞质[Ca2+]足够高时才表现出激动剂活性。即使存在高细胞质[Ca2+] (65 μ M)， AMP也不能完全打开通道，在2 mM AMP下观察到的最大打开概率（Po）约为0.3。3超过最大激活水平的AMP会导致通道失活我们的实验表明，AMP是一种激动剂，对心脏RyR上ATP位点的作用非常低，因此它是ATP诱导的Po增加的有效拮抗剂。我们的研究表明，腺嘌呤类化合物的核糖环5′-碳上附着的磷酸盐数量决定了配体增加心脏RyR Po的效果。在这个位置上取代基团可能导致在RyR上的ATP位点上鉴定出有效的拮抗剂。
1 We have investigated the ability of AMP to modulate the native sheep cardiac ryanodine receptor (RyR) channel at various cytosolic [Ca2+]. Channels were incorporated into planar phospholipid bilayers and current fluctuations through the bilayer were monitored under voltage damp conditions.2 We demonstrate that AMP only exhibits agonist activity if the cytosolic [Ca2+] is sufficiently high. Even in the presence of a high cytosolic [Ca2+] (65 mu M), AMP cannot fully open the channel and the maximum open probability (Po) observed is approximately 0.3 at 2 mM AMP.3 Concentrations of AMP above the maximally activating level cause inactivation of the channel.4 Our experiments indicate that AMP is an agonist with such low efficacy at the ATP sites on the cardiac RyR that it is effectively an antagonist of ATP-induced increases in Po. Our study demonstrates that the number of phosphates attached to the 5'-carbon of the ribose ring of adenine-based compounds determines the efficacy of the ligand to increase the Po of the cardiac RyR. Substitution of groups at this position may lead to the identification of potent antagonists at ATP sites on RyR.