So Christopher H, Verma Vaneeta, O'Dowd Brian F, George Susan R
Department of Pharmacology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
Mol Pharmacol. 2007 Aug;72(2):450-62. doi: 10.1124/mol.107.034884. Epub 2007 May 22.
When dopamine D1 and D2 receptors were coactivated in D1-D2 receptor hetero-oligomeric complexes, a novel phospholipase C-mediated calcium signal was generated. In this report, desensitization of this Gq/11-mediated calcium signal was demonstrated by pretreatment with dopamine or with the D1-selective agonist (+/-)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297) or the D2-selective agonist quinpirole. Desensitization of the calcium signal mediated by D1-D2 receptor hetero-oligomers was initiated by agonist occupancy of either receptor subtype even though the signal was generated only by occupancy of both receptors. The efficacy, potency, and rate of calcium signal desensitization by agonist occupancy of the D1 receptor (t1/2, approximately 1 min) was far greater than by the D2 receptor (t1/2, approximately 10 min). Desensitization of the calcium signal was not mediated by depletion of calcium stores or internalization of the hetero-oligomer and was not decreased by inhibiting second messenger-activated kinases. The involvement of G protein-coupled receptor kinases 2 or 3, but not 5 or 6, in the desensitization of the calcium signal was shown, occurring through a phosphorylation independent mechanism. Inhibition of Gi protein function associated with D2 receptors increased D1 receptor-mediated desensitization of the calcium signal, suggesting that cross-talk between the signals mediated by the activation of different G proteins controlled the efficacy of calcium signal desensitization. Together, these results demonstrate the desensitization of a signal mediated only by hetero-oligomerization of two G protein-coupled receptors that was initiated by agonist occupancy of either receptor within the hetero-oligomer, albeit with differences in desensitization profiles observed.
当多巴胺D1和D2受体在D1-D2受体异源寡聚体复合物中共同激活时，会产生一种新型的磷脂酶C介导的钙信号。在本报告中，通过用多巴胺或D1选择性激动剂（±）-6-氯-7,8-二羟基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓氢溴酸盐（SKF-81297）或D2选择性激动剂喹吡罗预处理，证明了这种Gq/11介导的钙信号脱敏。由D1-D2受体异源寡聚体介导的钙信号脱敏是由任何一种受体亚型的激动剂占据引发的，尽管该信号仅由两种受体的同时占据产生。激动剂占据D1受体导致的钙信号脱敏的效力、效能和速率（半衰期约1分钟）远大于D2受体（半衰期约10分钟）。钙信号脱敏不是由钙库耗竭或异源寡聚体内化介导的，也不会因抑制第二信使激活的激酶而降低。结果表明，G蛋白偶联受体激酶2或3而非5或6参与了钙信号脱敏，其通过非磷酸化机制发生。与D2受体相关的Gi蛋白功能抑制增加了D1受体介导的钙信号脱敏，表明由不同G蛋白激活介导的信号之间的串扰控制了钙信号脱敏的效能。总之，这些结果证明了仅由两种G蛋白偶联受体异源寡聚化介导的信号脱敏，该脱敏由异源寡聚体内任何一种受体的激动剂占据引发，尽管观察到脱敏特征存在差异。
