Regulation of dopamine D3 receptors by protein-protein interactions

Abstract

Gαi/o protein-coupled dopamine D3 receptors (D3Rs) are preferentially expressed in the limbic system, including the nucleus accumbens. This situates the receptor well in the regulation of limbic function and in the pathogenesis of various neuropsychiatric and neurodegenerative disorders. The intracellular domains of the receptor, mainly the large third intracellular loop and the intracellular C-terminal tail, interact with multiple submembranous proteins. These interactions are critical for the control of surface expression of the receptor and the efficacy of receptor signaling. Recently, a synapse-enriched protein kinase, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), has been found to interact with D3R in the above mentioned interaction model. CaMKII directly binds to the N-terminal of the third loop of D3R. This binding is Ca²⁺-dependent and is sustained by the autophosphorylation of the kinase. In rat accumbal neurons, the increase in Ca²⁺ level induces the recruitment of CaMKII to D3R, and CaMKII phosphorylates the receptor at a specific serine site. The CaMKII-induced phosphorylation could inhibit the receptor function and further regulate the behavioral response to the psychostimulant cocaine. These findings reveal a prototypic protein association model between a G protein-coupled receptor and CaMKII. Through the dynamic protein-protein interactions, the abundance, turnover cycle, and function of D3R can be regulated by multiple signals and enzymatic proteins.

摘要

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。