Modulation of M4 muscarinic acetylcholine receptors by interacting proteins

Abstract

Protein-protein interactions represent an important mechanism for posttranslational modifications of protein expression and function. In brain cells, surface-expressed and membrane-bound neurotransmitter receptors are common proteins that undergo dynamic protein-protein interactions between their intracellular domains and submembranous regulatory proteins. Recently, the Gα_i/o-coupled muscarinic M4 receptor (M4R) has been revealed to be one of these receptors. Through direct interaction with the intracellular loops or C-terminal tails of M4Rs, M4R interacting proteins (M4RIPs) vigorously regulate the efficacy of M4R signaling. A synapse-enriched protein kinase, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), exemplifies a prototype model of M4RIPs, and is capable of binding to the second intracellular loop of M4Rs. Through an activity- and phosphorylation-dependent mechanism, CaMKII potentiates the M4R/Gα_i/o-mediated inhibition of M4R efficacy in inhibiting adenylyl cyclase and cAMP production. In striatal neurons where M4Rs are most abundantly expressed, M4RIPs dynamically control M4R activity to maintain a proper cholinergic tone in these neurons. This is critical for maintaining the acetylcholine-dopamine balance in the basal ganglia, which determines the behavioral responsiveness to dopamine stimulation by psychostimulants.

摘要

蛋白-蛋白间的相互作用可以调控蛋白的表达及其功能。 在脑细胞中, 胞内蛋白常与膜表面受体的胞内区域结合来调节受体的表达和功能。 已有研究表明, Gαi/o 蛋白偶联的M4受体常受多种结合蛋白的调节。 这些结合蛋白通过与受体位于胞浆的区域结合来调节M4受体信号通路的传导效率。 钙离子/钙调蛋白依赖的蛋白激酶(Ca²⁺/calmodulin-dependent protein kinase II, CaMKII)是近年来发现的一种主要密集于突触的蛋白激酶, 与M4 受体的胞内第二个内环相结合。 CaMKII 通过磷酸化M4 受体来增强M4 受体通路对环腺苷酶的抑制作用, 进而减少cAMP 的合成。 在纹状体神经元中, M4受体结合蛋白动态控制M4受体的活性, 从而在这些细胞中维持适当的胆碱传导信号通路的活性。 可控的胆碱信号通路在维持基底节神经元内胆碱与多巴胺信号的平衡中有至关重要的作用, 并由此决定机体对精神兴奋剂引起的多巴胺刺激反应的灵敏度。