| First Author | Morton RA | Year | 2015 |
| Journal | Br J Pharmacol | Volume | 172 |
| Issue | 16 | Pages | 4066-77 |
| PubMed ID | 25989383 | Mgi Jnum | J:326649 |
| Mgi Id | MGI:7316535 | Doi | 10.1111/bph.13197 |
| Citation | Morton RA, et al. (2015) Agonist- and antagonist-induced up-regulation of surface 5-HT3 A receptors. Br J Pharmacol 172(16):4066-77 |
| abstractText | BACKGROUND AND PURPOSE: The 5-HT3 receptor is a member of the pentameric ligand-gated ion channel family and is pharmacologically targeted to treat irritable bowel syndrome and nausea/emesis. Furthermore, many antidepressants elevate extracellular concentrations of 5-HT. This study investigates the functional consequences of exposure of recombinant 5-HT3 A receptors to agonists and antagonists. EXPERIMENTAL APPROACH: We used HEK cells stably expressing recombinant 5-HT3 A receptors and the ND7/23 (mouse neuroblastoma/dorsal root ganglion hybrid) cell line, which expresses endogenous 5-HT3 receptors. Surface expression of recombinant 5-HT3 A receptors, modified to contain the bungarotoxin (BTX) binding sequence, was quantified using fluorescence microscopy to image BTX-conjugated fluorophores. Whole cell voltage-clamp electrophysiology was used to measure the density of current mediated by 5-HT3 A receptors. KEY RESULTS: 5-HT3 A receptors were up-regulated by the prolonged presence of agonists (5-HT and m-chlorophenylbiguanide) and antagonists (MDL-72222 and morphine). The up-regulation of 5-HT3 A receptors by 5-HT and MDL-72222 was time- and concentration-dependent but was independent of newly translated receptors. The phenomenon was observed for recombinant rodent and human 5-HT3 A receptors and for endogenous 5-HT3 receptors in neuronal ND7/23 cells. CONCLUSIONS AND IMPLICATIONS: Up-regulation of 5-HT3 A receptors, following exposure to either agonists or antagonists suggests that this phenomenon may occur in response to different therapeutic agents. Medications that elevate 5-HT levels, such as the antidepressant inhibitors of 5-HT reuptake and antiemetic inhibitors of 5-HT3 receptor function, may both raise receptor expression. However, this will require further investigation in vivo. |
