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激动剂诱导的β2肾上腺素能受体反向激动剂效能调节

Agonist-induced modulation of inverse agonist efficacy at the beta 2-adrenergic receptor.

作者信息

Chidiac P, Nouet S, Bouvier M

机构信息

Département de Biochimie, Université de Montréal, Canada.

出版信息

Mol Pharmacol. 1996 Sep;50(3):662-9.

PMID:8794908
Abstract

Sustained stimulation of several G protein-coupled receptors is known to lead to a reduction in the signaling efficacy. This phenomenon, named agonist-induced desensitization, has been best studied for the beta 2-adrenergic receptor (AR) and is characterized by a decreased efficacy of beta-adrenergic agonists to stimulate the adenylyl cyclase activity. Recently, several beta-adrenergic ligands were found to inhibit the spontaneous agonist-independent activity of the beta 2AR. These compounds, termed inverse agonists, have different inhibitory efficacies, ranging from almost neutral antagonists to full inverse agonists. The current study was undertaken to determine whether, as is the case for agonists, desensitization can affect the efficacies of inverse agonists. Agonist-promoted desensitization of the human beta 2AR expressed in Sf9 cells potentiated the inhibitory actions of the inverse agonists, with the extent of the potentiation being inversely proportional to their intrinsic activity. For example, desensitization increased the inhibitory action of the weak inverse agonist labetalol by 29%, whereas inhibition of the spontaneous activity by the strong inverse agonist timolol was not enhanced by the desensitizing stimuli. Interestingly, dichloroisoproterenol acted stochastically as either a weak partial agonist or a weak inverse agonist in control conditions but always behaved as an inverse agonist after desensitization. These data demonstrate that like for agonists, the efficacies of inverse agonists can be modulated by a desensitizing treatment. Also, the data show that the initial state of the receptor can determine whether a ligand behaves as a partial agonist or an inverse agonist.

摘要

已知对几种G蛋白偶联受体的持续刺激会导致信号传导效率降低。这种现象被称为激动剂诱导的脱敏,对β2 -肾上腺素能受体(AR)的研究最为充分,其特征是β -肾上腺素能激动剂刺激腺苷酸环化酶活性的效率降低。最近,发现几种β -肾上腺素能配体可抑制β2AR的自发激动剂非依赖性活性。这些化合物被称为反向激动剂,具有不同的抑制效力,范围从几乎中性的拮抗剂到完全反向激动剂。本研究旨在确定与激动剂情况一样,脱敏是否会影响反向激动剂的效力。在Sf9细胞中表达的人β2AR的激动剂促进的脱敏增强了反向激动剂的抑制作用,增强程度与它们的内在活性成反比。例如,脱敏使弱反向激动剂拉贝洛尔的抑制作用增加了29%,而强反向激动剂噻吗洛尔对自发活性的抑制作用并未因脱敏刺激而增强。有趣的是,在对照条件下,二氯异丙肾上腺素随机表现为弱部分激动剂或弱反向激动剂,但在脱敏后始终表现为反向激动剂。这些数据表明,与激动剂一样,反向激动剂的效力可通过脱敏处理进行调节。此外,数据表明受体的初始状态可以决定一种配体表现为部分激动剂还是反向激动剂。

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