Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas 66045, USA.
J Neurochem. 2010 Jul;114(1):51-61. doi: 10.1111/j.1471-4159.2010.06721.x. Epub 2010 Mar 31.
Previous research suggests that brain oxidative stress and altered rodent locomotor behavior are linked. We observed bio-behavioral changes in methionine sulfoxide reductase A knockout mice associated with abnormal dopamine signaling. Compromised ability of these knockout mice to reduce methionine sulfoxide enhances accumulation of sulfoxides in proteins. We examined the dopamine D(2)-receptor function and expression, which has an atypical arrangement and quantity of methionine residues. Indeed, protein expression levels of dopamine D(2)-receptor were higher in knockout mice compared with wild-type. However, the binding of dopamine D(2)-receptor agonist was compromised in the same fractions of knockout mice. Coupling efficiency of dopamine D(2)-receptors to G-proteins was also significantly reduced in knockout mice, supporting the compromised agonist binding. Furthermore, pre-synaptic dopamine release in knockout striatal sections was less responsive than control sections to dopamine D(2)-receptor ligands. Behaviorally, the locomotor activity of knockout mice was less responsive to the inhibitory effect of quinpirole than wild-type mice. Involvement of specific methionine residue oxidation in the dopamine D(2)-receptor third intracellular loop is suggested by in vitro studies. We conclude that ablation of methionine sulfoxide reductase can affect dopamine signaling through altering dopamine D(2)-receptor physiology and may be related to symptoms associated with neurological disorders and diseases.
先前的研究表明，大脑氧化应激与啮齿动物运动行为改变有关。我们观察到蛋氨酸亚砜还原酶 A 敲除小鼠的生物行为变化与异常多巴胺信号有关。这些敲除小鼠还原蛋氨酸亚砜的能力受损，导致蛋白质中亚砜的积累增加。我们检查了多巴胺 D2-受体的功能和表达，其具有非典型的排列和蛋氨酸残基数量。事实上，与野生型相比，多巴胺 D2-受体的蛋白表达水平在敲除小鼠中更高。然而，在相同的敲除小鼠部分，多巴胺 D2-受体激动剂的结合受到了损害。多巴胺 D2-受体与 G 蛋白的偶联效率在敲除小鼠中也显著降低，支持了激动剂结合受损。此外，与对照部分相比，敲除纹状体部分的多巴胺释放对多巴胺 D2-受体配体的反应性较低。在行为上，敲除小鼠的运动活性对喹吡罗的抑制作用的反应性低于野生型小鼠。体外研究表明，多巴胺 D2-受体第三细胞内环中特定蛋氨酸残基氧化的参与。我们得出结论，蛋氨酸亚砜还原酶的缺失可能通过改变多巴胺 D2-受体的生理学来影响多巴胺信号，并可能与与神经紊乱和疾病相关的症状有关。
