β1-和β2-肾上腺素受体介导的功能反应的明显差异脱敏机制综述

K. J. Broadley
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引用次数: 19

摘要

通过β1-和β2肾上腺素受体(β1ARs和β2ARs)介导的反应是否在长时间或反复暴露于激动剂后表现出相同程度的脱敏,一直存在相当大的争议。2提供了β1ARs功能反应的选择性脱敏和结合位点丢失的例子。同样,我们也给出了β2ARs选择性脱敏和下调的例子。这篇综述探讨了β ar介导的受体亚型选择性脱敏是否可能发生,以及即使在同一亚型中,是否也可能存在组织选择性脱敏。考虑了功能反应的明显选择性脱敏可能发生的可能原因,并将其分为方法学和非方法学因素。讨论的方法学因素包括:用于诱导脱敏的激动剂浓度和构建孵育后浓度-反应曲线(CRC)之前的冲洗时间,从时间匹配的对照中校正CRC的需要,以及绘制CRC的方法。5 .考虑了四个非方法学因素。首先,不同受体储备在各组织反应中的作用可能对脱敏是否明显有重要影响;一个大的储备将使脱敏不太可能明显。其次,脱敏发生的位点不止一个;受体从腺苷酸环化酶激活中解偶联,在环amp依赖性蛋白激酶的刺激水平上存在额外的位点,β ar可能最终下调。这些过程可能因组织和条件的不同而不同,这可能影响组织之间是否发生差异脱敏。第三,激动剂洗脱后脱敏的明显程度取决于再敏的速率。克服这一问题的实验描述了在激动剂持续存在下βAR脱敏。最后,讨论了PDE上调在脱敏中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Review of mechanisms involved in the apparent differential desensitization of β1- and β2-adrenoceptor-mediated functional responses

1 There has been considerable debate whether responses mediated via β1- and β2-adrenoceptors (β1ARs and β2ARs) display the same degree of desensitization after prolonged or repeated exposure to agonists.

2 Examples are provided for selective desensitization of functional responses and loss of binding sites for β1ARs. Equally, examples are given of selective desensitization and down-regulation involving β2ARs.

3 This review examines whether receptor subtype-selective desensitization of βAR-mediated responses can occur and whether even within the same subtype, there may be tissue-selective desensitization. Possible reasons why apparent selectivity of desensitization of functional responses may occur are considered and are divided into methodological and non-methodological factors.

4 Methodological factors discussed are: the concentration of agonist used for inducing desensitization and the washout times before construction of the post-incubation concentration-response curve (CRC), the need for correction of CRCs from time-matched controls, and the methods adopted for plotting CRCs.

5 Four non-methodological factors are considered. Firstly, the roles of different receptor reserves for the responses of each tissue can have an important effect on whether desensitization is apparent; a large reserve will make desensitization less likely to be apparent. Secondly, there is more than one site at which desensitization occurs; receptors are uncoupled from adenylyl cyclase activation, there is an additional site at the level of stimulation of cyclic AMP-dependent protein kinase and βARs may ultimately be down-regulated. These processes may differ depending on the tissue and conditions and this may influence whether differential desensitization occurs between tissues. Thirdly, the apparent degree of desensitization after washout of an agonist can depend upon the rate of resensitization. Experiments to overcome this problem are described which demonstrate βAR desensitization in the continued presence of agonist. Finally, the role of up-regulation of PDE in desensitization is discussed.

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