title: Which agonist properties are important for the activation of 5-HT3A receptors?
abstract: OBJECTIVE
  Why do anesthetics not activate excitatory ligand-gated ion channels such as 5-HT3 receptors in contrast to inhibitory ligand-gated ion channels? This study examines the actions of structural closely-related 5-HT derivatives and 5-HT constituent parts on 5-HT3A receptors with the aim of finding simpler if not minimal agonists and thus determining requirements for successful agonist action.
  
  
  METHODS
  Responses to 5-HT derivatives of human 5-HT3A receptors stably expressed in HEK 293 cells have been examined with the patch-clamp technique in the outside-out configuration combined with a fast solution exchange system.
  
  
  RESULTS
  Phenol, pyrrole and alkyl amines, constituents of 5-HT, even at high concentrations, cannot activate 5-HT3A receptors but they can inhibit them. To date, tyramines are the smallest known agonists. However, an aromatic ring is not required for activation as acetylcholine is also an agonist of similar strength.
  
  
  CONCLUSIONS
  Simultaneous interactions of adequate strength at two separate subsites within the 5-HT binding domain appear to be essential for successful agonist function. Anesthetics either fail to achieve this or the activation they produce is so weak that it is masked by a comparatively very strong inhibition.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany. Electronic address: merle.meiboom@web.de.
authors.forename: M F
authors.initials: MF
authors.lastname: Meiboom
authors.forename: M
authors.initials: M
authors.lastname: Barann
authors.forename: S
authors.initials: S
authors.lastname: Witten
authors.forename: K
authors.initials: K
authors.lastname: Groeneveld
authors.forename: B W
authors.initials: BW
authors.lastname: Urban
mesh_terms: D000588:Amines / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D018408:Patch-Clamp Techniques; D019800:Phenol / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects* / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000588:Amines; D011758:Pyrroles; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists; D019800:Phenol
keywords: 5-Hydroxytryptamine derivative; Agonist; Anesthetic; Human 5-HT(3A) receptor; Patch-clamp; Tyramine