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慢性暴露期间5-羟色胺（5-HT）的细胞隔离会因其随后的释放而延迟5-HT3受体的再敏化。

5-Hydroxytryptamine (5-HT) cellular sequestration during chronic exposure delays 5-HT3 receptor resensitization due to its subsequent release.

作者信息

Hothersall J Daniel, Alexander Amy, Samson Andrew J, Moffat Christopher, Bollan Karen A, Connolly Christopher N

机构信息

Medical Research Institute, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom.

Medical Research Institute, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom.

出版信息

J Biol Chem. 2014 Nov 14;289(46):32020-32029. doi: 10.1074/jbc.M114.594796. Epub 2014 Oct 3.

DOI:10.1074/jbc.M114.594796
PMID:25281748
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4231679/
Abstract

The serotonergic synapse is dynamically regulated by serotonin (5-hydroxytryptamine (5-HT)) with elevated levels leading to the down-regulation of the serotonin transporter and a variety of 5-HT receptors, including the 5-HT type-3 (5-HT3) receptors. We report that recombinantly expressed 5-HT3 receptor binding sites are reduced by chronic exposure to 5-HT (IC50 of 154.0 ± 45.7 μM, t½ = 28.6 min). This is confirmed for 5-HT3 receptor-induced contractions in the guinea pig ileum, which are down-regulated after chronic, but not acute, exposure to 5-HT. The loss of receptor function does not involve endocytosis, and surface receptor levels are unaltered. The rate and extent of down-regulation is potentiated by serotonin transporter function (IC50 of 2.3 ± 1.0 μM, t½ = 3.4 min). Interestingly, the level of 5-HT uptake correlates with the extent of down-regulation. Using TX-114 extraction, we find that accumulated 5-HT remains soluble and not membrane-bound. This cytoplasmically sequestered 5-HT is readily releasable from both COS-7 cells and the guinea pig ileum. Moreover, the 5-HT level released is sufficient to prevent recovery from receptor desensitization in the guinea pig ileum. Together, these findings suggest the existence of a novel mechanism of down-regulation where the chronic release of sequestered 5-HT prolongs receptor desensitization.

摘要

血清素能突触受到血清素（5-羟色胺，5-HT）的动态调节，血清素水平升高会导致血清素转运体以及多种5-HT受体（包括5-HT 3型受体）下调。我们报告称，重组表达的5-HT 3受体结合位点会因长期暴露于5-HT而减少（半数抑制浓度为154.0±45.7μM，半衰期为28.6分钟）。这在豚鼠回肠中5-HT 3受体诱导的收缩中得到证实，长期而非急性暴露于5-HT后，该收缩反应会下调。受体功能的丧失不涉及内吞作用，表面受体水平未改变。血清素转运体功能可增强下调的速率和程度（半数抑制浓度为2.3±1.0μM，半衰期为3.4分钟）。有趣的是，5-HT摄取水平与下调程度相关。通过TX-114萃取，我们发现积累的5-HT仍可溶且不与膜结合。这种细胞质中隔离的5-HT很容易从COS-7细胞和豚鼠回肠中释放出来。此外，释放的5-HT水平足以阻止豚鼠回肠中受体脱敏的恢复。总之，这些发现表明存在一种新的下调机制，即隔离的5-HT的慢性释放会延长受体脱敏。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d6/4231679/fd2d47e8950d/zbc0511401590005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d6/4231679/8a2e319f68ec/zbc0511401590001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d6/4231679/05fc818a1fed/zbc0511401590002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d6/4231679/ee37b7c8cb20/zbc0511401590003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d6/4231679/5b0de5269bf1/zbc0511401590004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d6/4231679/fd2d47e8950d/zbc0511401590005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d6/4231679/8a2e319f68ec/zbc0511401590001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d6/4231679/05fc818a1fed/zbc0511401590002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d6/4231679/ee37b7c8cb20/zbc0511401590003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d6/4231679/5b0de5269bf1/zbc0511401590004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d6/4231679/fd2d47e8950d/zbc0511401590005.jpg

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