人类足月子宫肌层的β3肾上腺素能受体而非β2肾上腺素能受体在持续激动剂刺激后对脱敏具有抗性。
The human near-term myometrial beta 3-adrenoceptor but not the beta 2-adrenoceptor is resistant to desensitisation after sustained agonist stimulation.
作者信息
Rouget C, Breuiller-Fouché M, Mercier F J, Leroy M J, Loustalot C, Naline E, Frydman R, Croci T, Morcillo E J, Advenier C, Bardou M
机构信息
UPRES EA220-Pharmacology, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, Paris 75006, France.
出版信息
Br J Pharmacol. 2004 Mar;141(5):831-41. doi: 10.1038/sj.bjp.0705616. Epub 2004 Feb 9.
Abstract
- In order to compare the beta(2)- and beta(3)-adrenoceptor (beta-AR) desensitisation process in human near-term myometrium, we examined the influence of a pretreatment of myometrial strips with either a beta(2)- or a beta(3)-AR agonist (salbutamol or SR 59119A, respectively, both at 10 microm, for 5 and 15 h) on the relaxation and the cyclic adenosine monophosphate (cAMP) production induced by these agonists. 2. To assess some of the mechanisms potentially implicated in the beta-AR desensitisation process, we studied the influence of such treatment on the number of beta(2)- and beta(3)-AR binding sites, the beta(2)- and beta(3)-AR transcripts expression and the phosphodiesterase 4 (PDE4) activity. 3. Salbutamol, but not SR 59119A, concentration-response curve (CRC) was shifted by a 15 h salbutamol preincubation, with a significant difference in -log EC(20) values (6.31+/-0.13 vs 5.58+/-0.24, for control and 15 h salbutamol pretreatment, respectively, P<0.05). Neither salbutamol nor SR 59119A CRCs were modified after a 15 h preincubation with SR 59119A. 4. A 15 h exposure of myometrial strips to salbutamol significantly reduced the salbutamol-induced (0.60+/-0.26 vs 1.54+/-0.24 pmol mg(-1) protein, P<0.05), but not the SR 59119A-induced, cAMP production. No decrease in cAMP production was observed after a 15 h SR 59119A exposure. 5. A 15 h salbutamol exposure of myometrial strips significantly reduced the beta(2)- but not the beta(3)-AR binding site density, whereas no decrease in the number of beta(2)- and beta(3)-AR binding sites was observed after a 15 h SR 59119A treatment. 6. Neither PDE4 activity nor the beta(2)- and beta(3)-AR mRNA expression levels were affected by salbutamol or SR 59119A treatments. 7. Our results indicate that beta(3)-AR, but not beta(2)-AR, are resistant to the agonist-induced desensitisation. In our model, beta(2)-AR desensitisation is mediated by a decreased number of beta(2)-AR that was not explained by transcriptional regulation of the receptor.
摘要
- 为了比较人足月子宫肌层中β₂ - 和β₃ - 肾上腺素能受体（β - AR）的脱敏过程，我们研究了用β₂ - 或β₃ - AR激动剂（分别为沙丁胺醇或SR 59119A，均为10 μmol，作用5小时和15小时）预处理子宫肌条对这些激动剂诱导的舒张和环磷酸腺苷（cAMP）产生的影响。2. 为了评估β - AR脱敏过程中可能涉及的一些机制，我们研究了这种处理对β₂ - 和β₃ - AR结合位点数量、β₂ - 和β₃ - AR转录本表达以及磷酸二酯酶4（PDE4）活性的影响。3. 15小时的沙丁胺醇预孵育使沙丁胺醇的浓度 - 反应曲线（CRC）发生了偏移，但SR 59119A未出现这种情况， - log EC₂₀值存在显著差异（对照组和15小时沙丁胺醇预处理组分别为6.31±±± 0.13和5.58±±± 0.24，P < 0.05）。用SR 59119A预孵育15小时后，沙丁胺醇和SR 59119A的CRC均未改变。4. 将子宫肌条暴露于沙丁胺醇15小时可显著降低沙丁胺醇诱导的cAMP产生（0.60±±± 0.26对1.54±±± 0.24 pmol mg⁻¹蛋白，P < 0.05），但对SR 59119A诱导者无影响。暴露于SR 59119A 15小时后未观察到cAMP产生的减少。5. 将子宫肌条暴露于沙丁胺醇15小时可显著降低β₂ - 但不影响β₃ - AR结合位点密度，而用SR
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