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: As high levels of 5-HT are observed within the gut, we investigated whether chronic exposure to 5-HT led to a ligand-induced down-regulation of receptor function in the intact guinea pig ileum. Specific 5-HT3 receptor activation was monitored by the contractile responses induced by the selective agonist 2-ME. Acute exposure to 5-HT (100 μm) caused a robust contraction and rapid receptor desensitization (Fig. 2A, center trace) which recovered quickly after washing (<10 min, not shown). In contrast, chronic exposure to 5-HT (100 μm, 60 min), followed by washout in a drug-free buffer for 10 min (to allow receptor resensitization) caused a significant decrease (to 48.6 ± 25.0%, Fig. 2B) in the magnitude of subsequent 2-ME-evoked contractions (p < 0.001, ANOVA, n = 28) (Fig. 2A, right trace) compared with the pretreatment contraction (Fig. 2A, left trace). After removal of 5-HT (60 min) the responses to 2-ME were fully recoverable (Fig. 2B). To investigate the specificity of the 5-HT3 functional loss, contractions evoked by ACh were also quantified. In this case the magnitude of ACh responses were unaffected by chronic 5-HT treatment (p > 0.05; ANOVA, n = 14; Fig. 2C), verifying that the tissue was still capable of undergoing contractions and that the down-regulation was specific to 5-HT3 receptors. An individual example of 5-HT3 functional loss is shown (Fig. 2A) where a pre-pulse of 2-ME and ACh precedes 5-HT chronic (60 min) exposure (note early receptor desensitization). After the chronic exposure to 5-HT, 2-ME, but not ACh, responses were reduced.
Affiliation: From the Medical Research Institute, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom.