Carbetocin is a Functional Selective Gq Agonist That Does Not Promote Oxytocin Receptor Recycling After Inducing β-Arrestin-Independent Internalisation
Carbetocin is a Functional Selective Gq Agonist That Does Not Promote Oxytocin Receptor Recycling After Inducing β-Arrestin-Independent Internalisation
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DOI：
10.1111/jne.12363
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发表时间：
2016-04-01
影响因子：
3.2
通讯作者：
Busnelli, M.
中科院分区：
文献类型：
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作者：
Passoni, I.;Leonzino, M.;Busnelli, M.
卡贝缩宫素是一种长效催产素类似物，据报道，它能引起有趣而奇特的行为效应。本研究探讨了卡贝缩宫素的分子药理学，旨在更好地了解其在大脑中作用的分子基础。使用生物发光共振能量转移生物传感器，我们表征了卡贝缩宫素对神经系统中表达的三种人类催产素/加压素受体的影响：催产素受体（OXTR）和加压素V1 a（V1 aR）和V1 b（V1 bR）受体。我们的研究结果表明：（i）卡贝缩宫素激活OXTR，但不激活V1 aR和V1 bR，在这两个位点上，卡贝缩宫素可能起拮抗剂的作用;（ii）卡贝缩宫素仅选择性激活OXTR/Gq通路，显示出很强的功能选择性;（iii）卡贝缩宫素是OXTR/Gq偶联的部分激动剂;（iv）卡贝缩宫素通过以前未报道的β-抑制蛋白-非依赖性通路促进OXTR内化;和（v）卡贝缩宫素不诱导OXTR再循环至质膜。总之，这些分子药理学特征将卡贝缩宫素鉴定为与内源性催产素相比显著不同的类似物，因此，卡贝缩宫素预期不会模拟脑中的催产素。卡贝缩宫素的这些独特特征是否可以用于治疗仍有待确定。
Carbetocin, a long-acting oxytocin analogue, has been reported to elicit interesting and peculiar behavioural effects. The present study investigated the molecular pharmacology of carbetocin, aiming to better understand the molecular basis of its action in the brain. Using bioluminescence resonance energy transfer biosensors, we characterised the effects of carbetocin on the three human oxytocin/vasopressin receptors expressed in the nervous system: the oxytocin receptor (OXTR) and the vasopressin V1a (V1aR) and V1b (V1bR) receptors. Our results indicate that (i) carbetocin activates the OXTR but not the V1aR and V1bR at which it may act as an antagonist; (ii) carbetocin selectively activates only the OXTR/Gq pathway displaying a strong functional selectivity; (iii) carbetocin is a partial agonist at the OXTR/Gq coupling; (iv) carbetocin promotes OXTR internalisation via a previously unreported beta-arrestin-independent pathway; and (v) carbetocin does not induce OXTR recycling to the plasma membrane. Altogether, these molecular pharmacology features identify carbetocin as a substantially different analogue compared to the endogenous oxytocin and, consequently, carbetocin is not expected to mimic oxytocin in the brain. Whether these unique features of carbetocin could be exploited therapeutically remains to be established.