人CRF2(a)受体信号的脱敏由激动剂效力和β阻滞2募集控制。

Richard L. Hauger , J. Alberto Olivares-Reyes , Sandra Braun , Judith Hernandez-Aranda , Christine C. Hudson , Eric Gutknecht , Frank M. Dautzenberg , Robert H. Oakley
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引用次数: 12

摘要

主要目的是确定激动剂对CRF2(a)受体功能的特异性调节。将人视网膜母细胞瘤Y79细胞暴露于选择性(UCN2、UCN3或应激因子)和非选择性(UCN1或sauvagine)激动剂中,以快速、浓度依赖的方式显著脱敏CRF2(a)受体。在弱受体激动剂CRF的反应中,脱敏的速度相对较慢,幅度较小。CRF、cortagine或应激素1- a刺激CRF1受体脱敏对CRF2(a)受体环AMP信号没有影响。相反,UCN2或UCN3对CRF2(a)受体的脱敏并不会交叉脱敏gs偶联CRF1受体信号。在转染的HEK293细胞中,UCN2、UCN3或CRF激活CRF2(a)受体,导致受体磷酸化和内化,与激动剂的效力成正比。蛋白激酶A和酪蛋白激酶均未介导CRF2(A)受体磷酸化或脱敏。HEK293或U2OS细胞暴露于UCN2或UCN3 (100 nM)时,βarrestin2与膜CRF2(a)受体发生强烈的移位和共定位,而CRF (1 μM)仅产生弱的βarrestin2募集。然而,β阻滞蛋白2并没有随受体内化,这表明瞬时CRF2(a)受体-阻滞蛋白复合物在细胞膜上或细胞膜附近解离。由于βarrestin2基因缺失可上调MEF细胞中gs偶联CRF2(a)受体信号,因此βarrestin2机制可抑制尿皮质素激活的gs偶联CRF2(a)受体信号。我们进一步得出结论,同源CRF2(a)受体脱敏的速率和程度受激动剂特异性机制的控制,这些机制影响GRK磷酸化、β阻滞2募集和内化,从而产生独特的信号转导谱,对应激反应产生不同的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Desensitization of human CRF2(a) receptor signaling governed by agonist potency and βarrestin2 recruitment

Desensitization of human CRF2(a) receptor signaling governed by agonist potency and βarrestin2 recruitment

The primary goal was to determine agonist-specific regulation of CRF2(a) receptor function. Exposure of human retinoblastoma Y79 cells to selective (UCN2, UCN3 or stresscopins) and non-selective (UCN1 or sauvagine) agonists prominently desensitized CRF2(a) receptors in a rapid, concentration-dependent manner. A considerably slower rate and smaller magnitude of desensitization developed in response to the weak agonist CRF. CRF1 receptor desensitization stimulated by CRF, cortagine or stressin1-A had no effect on CRF2(a) receptor cyclic AMP signaling. Conversely, desensitization of CRF2(a) receptors by UCN2 or UCN3 did not cross-desensitize Gs-coupled CRF1 receptor signaling. In transfected HEK293 cells, activation of CRF2(a) receptors by UCN2, UCN3 or CRF resulted in receptor phosphorylation and internalization proportional to agonist potency. Neither protein kinase A nor casein kinases mediated CRF2(a) receptor phosphorylation or desensitization. Exposure of HEK293 or U2OS cells to UCN2 or UCN3 (100 nM) produced strong βarrestin2 translocation and colocalization with membrane CRF2(a) receptors while CRF (1 μM) generated only weak βarrestin2 recruitment. βarrestin2 did not internalize with the receptor, however, indicating that transient CRF2(a) receptor–arrestin complexes dissociate at or near the cell membrane. Since deletion of the βarrestin2 gene upregulated Gs-coupled CRF2(a) receptor signaling in MEF cells, a βarrestin2 mechanism restrains Gs-coupled CRF2(a) receptor signaling activated by urocortins. We further conclude that the rate and extent of homologous CRF2(a) receptor desensitization are governed by agonist-specific mechanisms affecting GRK phosphorylation, βarrestin2 recruitment, and internalization thereby producing unique signal transduction profiles that differentially affect the stress response.

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来源期刊
Regulatory Peptides
Regulatory Peptides 医学-内分泌学与代谢
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审稿时长
2 months
期刊介绍: Regulatory Peptides provides a medium for the rapid publication of interdisciplinary studies on the physiology and pathology of peptides of the gut, endocrine and nervous systems which regulate cell or tissue function. Articles emphasizing these objectives may be based on either fundamental or clinical observations obtained through the disciplines of morphology, cytochemistry, biochemistry, physiology, pathology, pharmacology or psychology.
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