The Beta-Arrestin-Biased Dopamine D2 Receptor Ligand, UNC9994, Is a Partial Agonist at G-Protein-Mediated Potassium Channel Activation
The Beta-Arrestin-Biased Dopamine D2 Receptor Ligand, UNC9994, Is a Partial Agonist at G-Protein-Mediated Potassium Channel Activation
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DOI：
10.1093/ijnp/pyy059
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发表时间：
2018-12-01
影响因子：
4.8
通讯作者：
Sahlholm, Kristoffer
中科院分区：
文献类型：
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作者：
Agren, Richard;Arhem, Peter;Sahlholm, Kristoffer
背景：之前的证据表明，UNC9994 是多巴胺 D-2 受体的 β-arrestin2 选择性激动剂，缺乏激活和拮抗 G 蛋白依赖性信号传导的能力。然而，只有一个实验室使用单一测定法报告了这一点。方法：我们在非洲爪蟾卵母细胞中使用 G 蛋白偶联的内向整流钾通道激活来研究 UNC9994 诱导的多巴胺 D-2 受体和多巴胺 D-3 受体上 G 蛋白依赖性信号传导的调节。结果：在多巴胺 D-2 受体上，UNC9994 诱导 G 蛋白质耦合内向整流钾通道电流是多巴胺最大反应的 15%，EC50 为 185 nM。对于多巴胺 D-3 受体，配体引发了 89% 的最大多巴胺反应，EC50 为 62 nM。百日咳毒素消除了 G 蛋白偶联内向整流钾通道的激活。此外，UNC9994 拮抗多巴胺诱导的多巴胺 D-2 受体处的 G 蛋白偶联内向整流钾通道激活。结论：UNC9994 通过多巴胺 D-2 受体和多巴胺 D-3 受体处的百日咳毒素敏感 G 蛋白调节 G 蛋白偶联内向整流钾通道通道激活。这些发现可能对解释用该配体获得的数据有影响。
Background: Previous evidence suggests that UNC9994 is a beta-arrestin2-selective agonist at the dopamine D-2 receptor, lacking ability both to activate and antagonize G protein-dependent signaling. However, this has only been reported by one laboratory using a single assay.Methods: We used G protein-coupled inward rectifier potassium channel activation in Xenopus oocytes to investigate UNC9994-induced modulation of G protein-dependent signaling at dopamine D-2 receptor and dopamine D-3 receptor.Results: At dopamine D-2 receptor, UNC9994 induced G protein-coupled inward rectifier potassium channel currents that were 15% of the maximal response to dopamine, with an EC50 of 185 nM. At dopamine D-3 receptor, the ligand elicited 89% of the maximal dopamine response with an EC50 of 62 nM. Pertussis toxin abolished G protein-coupled inward rectifier potassium channel activation. Furthermore, UNC9994 antagonized dopamine-induced G protein-coupled inward rectifier potassium channel activation at dopamine D-2 receptor.Conclusions: UNC9994 modulates G protein-coupled inward rectifier potassium channel channel activation via pertussis toxin-sensitive G proteins at dopamine D-2 receptor and dopamine D-3 receptor. These findings may have implications for the interpretation of data obtained with this ligand.