Voltage‐gated Ca²⁺ (Ca_V) channels are crucial for neuronal excitability and synaptic transmission upon depolarization. Their properties in vivo are modulated by their interaction with a variety of scaffolding proteins. Such interactions can influence the function and localization of Ca_V channels, as well as their coupling to intracellular second messengers and regulatory pathways, thus amplifying their signaling potential. Among these scaffolding proteins, a subset of PDZ (postsynaptic density‐95, Drosophila discs‐large, and zona occludens)‐domain containing proteins play diverse roles in modulating Ca_V channel properties. At the presynaptic terminal, PDZ proteins enrich Ca_V channels in the active zone, enabling neurotransmitter release by maintaining a tight and vital link between channels and vesicles. In the postsynaptic density, these interactions are essential in regulating dendritic spine morphology and postsynaptic signaling cascades. In this review, we highlight the studies that demonstrate dynamic regulations of neuronal Ca_V channels by PDZ proteins. We discuss the role of PDZ proteins in controlling channel activity, regulating channel cell surface density, and influencing channel‐mediated downstream signaling events. We highlight the importance of PDZ protein regulations of Ca_V channels and evaluate the link between this regulatory effect and human disease.

中文翻译：

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与 PDZ 蛋白的相互作用使电压门控钙通道信号多样化。

电压门控 Ca ²⁺ (Ca _V ) 通道对于去极化时的神经元兴奋性和突触传递至关重要。它们在体内的特性是通过它们与各种支架蛋白的相互作用来调节的。这种相互作用可以影响 Ca _V通道的功能和定位，以及它们与细胞内第二信使和调节通路的耦合，从而放大它们的信号潜力。在这些支架蛋白中，PDZ（突触后密度-95、果蝇圆盘-大和封闭带）结构域的一个子集在调节 Ca _V通道特性方面发挥着不同的作用。在突触前末端，PDZ 蛋白富集 Ca _V激活区中的通道，通过保持通道和囊泡之间紧密而重要的联系来释放神经递质。在突触后密度中，这些相互作用对于调节树突棘形态和突触后信号级联至关重要。在这篇综述中，我们重点介绍了证明PDZ 蛋白对神经元 Ca _V通道动态调节的研究。我们讨论了 PDZ 蛋白在控制通道活性、调节通道细胞表面密度和影响通道介导的下游信号事件中的作用。我们强调了 Ca _V通道的 PDZ 蛋白调节的重要性，并评估了这种调节作用与人类疾病之间的联系。