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Gαi/o蛋白偶联的多巴胺受体D3在包括付隔核的边缘系统中丰富表达。其不仅能调节边缘系统功能,而且在神经精神疾病和神经退行性病变过程中起重要作用。D3受体的胞内结构,尤其是第三个细胞内环和C末端,可以和多个靠近细胞内膜的蛋白相互结合,以此来调控受体的膜表面表达及其功效。最近的研究发现,D3受体和蛋白激酶能够以此模型相互结合。突触富集的钙/钙调蛋白依赖的蛋白激酶II(CaMKII)直接与D3受体第三个细胞内环的N末端结合。这种结合是钙离子依赖的,并被CaMKII激酶的自我磷酸化所加强。在大鼠的付隔核神经元中,钙离子水平的升高能诱导CaMKII与D3结合,并磷酸化D3受体上特定的丝氨酸位点。CaMKII介导的受体磷酸化能抑制受体的功能,进而调节动物对可卡因兴奋剂的行为学反应。这些结果揭示了G蛋白偶联受体与CaMKII作用的一种新模式。蛋白间动态的结合使得D3受体的膜表达丰度、衰减周期和功能受到多种信号和酶蛋白的调节。
Gαi / o protein-coupled dopamine receptor D3 is abundantly expressed in the limbic system including the septal nucleus. It not only regulates the function of the limbic system but also plays an important role in the neuropsychiatric and neurodegenerative diseases. The intracellular structure of the D3 receptor, especially the third intracellular and C-terminal end, binds to multiple proteins near the cell’s inner membrane to regulate membrane surface expression of the receptor and its efficacy. Recent studies have found that D3 receptors and protein kinases bind to each other in this model. Synapse-enriched calcium / calmodulin-dependent protein kinase II (CaMKII) binds directly to the N-terminus of the third intracellular loop of the D3 receptor. This binding is calcium-dependent and potentiated by autophosphorylation of CaMKII kinase. In rat septal neurons, an increase in calcium levels induces CaMKII binding to D3 and phosphorylates specific serine sites on the D3 receptor. CaMKII-mediated receptor phosphorylation can inhibit the function of the receptor, thereby regulating the animal’s behavior response to cocaine stimulants. These results reveal a new mode of action of G-protein coupled receptors and CaMKII. The dynamic binding of proteins allows the abundance of membrane receptors at the D3 receptor, and the cycle and function of attenuation is regulated by various signals and enzyme proteins.