Ca2+-activated ryanodine binding: mechanisms of sensitivity and intensity modulation by Mg2+, caffeine, and adenine nucleotides.
Ca2+-activated ryanodine binding: mechanisms of sensitivity and intensity modulation by Mg2+, caffeine, and adenine nucleotides.
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DOI：
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发表时间：
1987-03
影响因子：
3.6
通讯作者：
I. Pessah;R. Stambuk;J. Casida
中科院分区：
文献类型：
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作者：
I. Pessah;R. Stambuk;J. Casida
Ca2+-ryanodine受体复合物是肌浆网（SR）末端池（TC）的一个功能单位，其蛋白质构成Ca2+释放通道，可能参与兴奋-收缩耦合。Ca2+, Mg2+，咖啡因和腺嘌呤核苷酸，而不是肌醇1,4,5-三磷酸，可能通过直接变构调节[3H]ryanodine结合位点对骨骼肌SR发挥其肌力作用。微摩尔Ca2+主要负责通过调节受体位点密度、亲和力和协同性来激活[3H]ryanodine结合。Mg2+通过直接与Ca2+竞争激活位点，降低了对Ca2+激活的敏感性。然而，Mg2+的抑制作用在β、γ -亚甲基腺苷5'-三磷酸（AMP-PCP; 1 mM）或咖啡因（20 mM）存在时被克服。咖啡因显著增加Ca2+激活位点对Ca2+的亲和力，而AMP-PCP或cAMP则提高了TC - SR通道的门控效率或开放状态的寿命。提出了Ca2+-ryanodine受体复合物的四个功能域的动力学模型：Ca2+调节域以微m亲和力结合Ca2+，主要负责以合作方式控制TC SR的Ca2+通道，并通过直接竞争激活位点被mM Mg2+抑制，该激活位点似乎含有关键的巯基；靠近通道的Ca2+激活生物碱结合域，以nM亲和力结合ryanodine，并在复合物形成时迅速闭合；该结构域结合咖啡因的亲和力较低（大于mM），并直接影响Ca2+调控位点的敏感性；和一个结合腺嘌呤核苷酸具有中等亲和力（小于mM）的结构域，不需要磷酸化，并增强Ca2+信号，触发Ca2+释放通道的打开。
The Ca2+-ryanodine receptor complex is a functional unit at the terminal cisternae (TC) of the sarcoplasmic reticulum (SR) whose proteins comprise the Ca2+ release channels which may be involved in excitation-contraction coupling. Ca2+, Mg2+, caffeine, and adenine nucleotides, but not inositol 1,4,5-trisphosphate, may exert their inotropic effects on skeletal muscle SR by direct allosteric modulation of the [3H]ryanodine-binding site. Micromolar Ca2+ is primarily responsible for activating [3H]ryanodine binding by regulating receptor site density, affinity, and cooperativity. Mg2+ reduces the sensitivity to Ca2+ activation by directly competing with Ca2+ for the activator site. However, inhibition by Mg2+ is overcome in the presence of beta,gamma-methyleneadenosine 5'-triphosphate (AMP-PCP; 1 mM) or caffeine (20 mM). Caffeine dramatically increases the affinity of the Ca2+ activator site for Ca2+, whereas AMP-PCP or cAMP enhances the gating efficiency or the lifetime of the open state of the TC SR channel. A kinetic model is proposed for four functional domains of the Ca2+-ryanodine receptor complex: the Ca2+-regulatory domain which binds Ca2+ with microM affinity is primarily responsible for gating the Ca2+ channel of the TC SR in a cooperative manner, and is inhibited by mM Mg2+ by direct competition for the activator site which appears to contain critical sulfhydryl groups; a Ca2+-activate alkaloid binding domain in close proximity to the channel which binds ryanodine with nM affinity and rapidly occludes upon complex formation; a domain which binds caffeine with low (greater than mM) affinity and directly influences the sensitivity of the Ca2+-regulatory site; and a domain which binds adenine nucleotides with intermediate affinity (less than mM), does not require phosphorylation, and intensifies the Ca2+ signal which triggers opening of the Ca2+-release channel.