5-Hydroxytryptamine (5-HT) cellular sequestration during chronic exposure delays 5-HT3 receptor resensitization due to its subsequent release.
Bottom Line: The loss of receptor function does not involve endocytosis, and surface receptor levels are unaltered.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.
Affiliation: From the Medical Research Institute, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom.Show MeSH
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Mentions: To determine if cells are capable of releasing the sequestered 5-HT, we investigated the release of 5-[3H]HT from COS-7 cells and the guinea pig ileum. COS-7 cells (no SERT) were loaded with 5-HT (300 μm, 0.1% 5-[3H]HT, 60 min), excess 5-HT was washed off, and cells were chased for 120 min. Under the experimental conditions in which we observed down-regulation of function (Figs. 1 and 3), the release of 5-HT reached low micromolar levels (Fig. 5A). To determine if the same pool of 5-HT exists within cells in native tissue where high 5-HT level can occur, we investigated 5-HT uptake (300 μm, 0.1% 3H-5-HT, 60 min) in guinea pig ileum segments. A 7-cm segment was turned inside out and incubated with 5-HT (100 μm, 0.16% 3H-5-HT, 60 min). Five equal sections were cut, and 5-HT release was monitored (in 1.5 ml) from each. Under these conditions, 5-HT is sequestered and released from the ileum in the low micromolar range (Fig. 5B).
Affiliation: From the Medical Research Institute, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom.