Many proteins are phosphorylated at more than one phosphorylation site to achieve precise tuning of protein function and/or integrate a multitude of signals into the activity of one protein. Increasing the number of phosphorylation sites significantly broadens the complexity of molecular mechanisms involved in processing multiple phosphorylation sites by one or more distinct kinases. The cardiac ryanodine receptor (RYR2) is a well-established multiple phospho-target of kinases activated in response to β-adrenergic stimulation because this Ca²⁺ channel is a critical component of Ca²⁺ handling machinery which is responsible for β-adrenergic enhancement of cardiac contractility. Our review presents a selective overview of the extensive, often conflicting, literature which focuses on identifying reliable lines of evidence to establish if multiple RYR2 phosphorylation is achieved randomly or in a specific sequence, and whether phosphorylation at individual sites is functionally specific and additive or similar and can therefore be substituted.

许多蛋白质在不止一个磷酸化位点被磷酸化，以实现蛋白质功能的精确调节和/或将多种信号整合到一种蛋白质的活性中。增加磷酸化位点的数量显着拓宽了通过一种或多种不同激酶处理多个磷酸化位点所涉及的分子机制的复杂性。心脏兰诺定受体（RYR2）是响应于β肾上腺素能刺激活化的激酶的良好建立的多个磷酸化的目标，因为这样的Ca ²⁺通道的Ca是一个关键组成部分²⁺负责β-肾上腺素能增强心脏收缩力的操作机械。我们的审查对广泛的、经常相互矛盾的文献进行了选择性的概述，重点是确定可靠的证据线，以确定多个 RYR2 磷酸化是随机实现的还是以特定顺序实现的，以及单个位点的磷酸化是否具有功能特异性和累加性或相似性并且因此可以被替换。