title: Agonist- and antagonist-induced up-regulation of surface 5-HT3 A receptors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA.|Department of Pharmacology and Physiology, George Washington University, Washington, DC, USA.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Morton
authors.affiliation: Institute of Academic Anaesthesia, Division of Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Baptista-Hon
authors.affiliation: Department of Pharmacology and Physiology, George Washington University, Washington, DC, USA.|Institute of Academic Anaesthesia, Division of Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: Tim G
authors.initials: TG
authors.lastname: Hales
authors.affiliation: Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA.|Department of Pharmacology and Physiology, George Washington University, Washington, DC, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Lovinger
mesh_terms: D000818:Animals; D001645:Biguanides / Q000494:pharmacology; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D051381:Rats; D044406:Receptors, Serotonin, 5-HT3 / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014326:Tropanes / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D001645:Biguanides; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014326:Tropanes; D012701:Serotonin; D009020:Morphine; C065734:1-(3-chlorophenyl)biguanide; C042253:bemesetron