Pessah I N, Stambuk R A, Casida J E
Mol Pharmacol. 1987 Mar;31(3):232-8.
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.
钙离子-兰尼碱受体复合物是肌浆网（SR）终末池（TC）处的一个功能单位，其蛋白质构成了可能参与兴奋-收缩偶联的钙离子释放通道。钙离子、镁离子、咖啡因和腺嘌呤核苷酸，而非肌醇1,4,5-三磷酸，可通过对[3H]兰尼碱结合位点的直接变构调节，对骨骼肌SR发挥其变力作用。微摩尔浓度的钙离子主要通过调节受体位点密度、亲和力和协同性来激活[3H]兰尼碱结合。镁离子通过与钙离子直接竞争激活位点来降低对钙离子激活的敏感性。然而，在存在β,γ-亚甲基腺苷5'-三磷酸（AMP-PCP；1 mM）或咖啡因（20 mM）的情况下，镁离子的抑制作用会被克服。咖啡因显著增加钙离子激活位点对钙离子的亲和力，而AMP-PCP或环磷酸腺苷（cAMP）则提高TC SR通道开放状态的门控效率或寿命。针对钙离子-兰尼碱受体复合物的四个功能结构域提出了一个动力学模型：以微摩尔亲和力结合钙离子的钙离子调节结构域主要负责以协同方式控制TC SR的钙离子通道，并通过直接竞争似乎含有关键巯基的激活位点而被毫摩尔浓度的镁离子抑制；一个紧邻通道的钙离子激活生物碱结合结构域，以纳摩尔亲和力结合兰尼碱，并在复合物形成后迅速封闭；一个以低（大于毫摩尔）亲和力结合咖啡因并直接影响钙离子调节位点敏感性的结构域；以及一个以中等亲和力（小于毫摩尔）结合腺嘌呤核苷酸、不需要磷酸化并增强触发钙离子释放通道开放的钙离子信号的结构域。
