Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Pharmacol Ther. 2018 May;185:99-121. doi: 10.1016/j.pharmthera.2017.12.004. Epub 2017 Dec 17.
A common feature of neurological and neuropsychiatric disorders is a breakdown in the integrity of intracellular signal transduction pathways. Dysregulation of ion channels and receptors in the cell membrane and the enzymatic mediators that link them to intracellular effectors can lead to synaptic dysfunction and neuronal death. However, therapeutic targeting of these ubiquitous signaling elements can lead to off-target side effects due to their widespread expression in multiple systems of the body. A-kinase anchoring proteins (AKAPs) are multivalent scaffolding proteins that compartmentalize a diverse range of receptor and effector proteins to streamline signaling within nanodomain signalosomes. A number of essential neurological processes are known to critically depend on AKAP-directed signaling and an understanding of the role AKAPs play in nervous system disorders has emerged in recent years. Selective targeting of AKAP protein-protein interactions may be a means to uncouple pathologically active signaling pathways in neurological disorders with a greater degree of specificity. In this review we will discuss the role of AKAPs in both regulating normal nervous system function and dysfunction associated with disease, and the potential for therapeutic targeting of AKAP signaling complexes.
神经和神经精神疾病的一个共同特征是细胞内信号转导途径的完整性出现故障。细胞膜中离子通道和受体的失调以及将它们与细胞内效应器连接的酶介质会导致突触功能障碍和神经元死亡。然而，由于这些普遍存在的信号元件在体内多个系统中广泛表达，因此针对这些无处不在的信号元件进行治疗可能会导致脱靶副作用。A-激酶锚定蛋白 (AKAP) 是多价支架蛋白，可将多种受体和效应蛋白分隔到纳米域信号小体中，以简化信号转导。已知许多重要的神经过程严重依赖于 AKAP 定向信号，近年来，人们对 AKAP 在神经系统疾病中的作用有了更多的了解。选择性靶向 AKAP 蛋白-蛋白相互作用可能是一种更具特异性的方法，可以将神经疾病中病理性激活的信号通路与更大程度的特异性解耦。在这篇综述中，我们将讨论 AKAP 在调节正常神经系统功能和与疾病相关的功能障碍中的作用，以及靶向 AKAP 信号复合物的潜在治疗方法。
