Selection of distinct conformational states of the 5-HT3 receptor by full and partial agonists.
1. 5-Hydroxytryptamine 5-HT3 receptor-mediated ion currents evoked by 5-HT, quaternary 5-HT (5-HTQ), meta-chlorophenylbiguanide (mCPBG), dopamine and tryptamine in N1E-115 mouse neuroblastoma cells have been investigated in whole-cell voltage clamp and single channel patch clamp experiments. 2. The concentration-dependent activation and desensitization of the ion currents evoked by the agonists yield the potency order: mCPBG > 5-HTQ approximately 5-HT >> tryptamine > dopamine, and the efficacy order: 5-HT approximately mCPBG approximately 5-HTQ >> dopamine approximately tryptamine. Thus, 5-HT, 5-HTQ and mCPBG are full agonists, whereas dopamine and tryptamine are partial agonists at the 5-HT3 receptor. 3. Full and partial agonists cause complete cross-desensitization and activate single channels with similar conductances and open lifetimes. This shows that full and partial agonists act on the same population of 5-HT3 receptors. 4. The time course of recovery from desensitization depends on the agonist used. Recovery from partial agonist-induced desensitization is single exponential, whereas the desensitization induced by full agonists recovers with sigmoid kinetics, suggesting at least 3 steps between 4 states. 5. During the process of recovery from cross-desensitization, the full agonists activate a larger fraction of the 5-HT3 receptors than the partial agonists, irrespective of the agonist used to induce desensitization. 6. It is concluded that full and partial agonists induce distinct desensitized states and, during recovery from desensitization, recognize distinct conformations of unoccupied 5-HT3 receptors. This conformational selection is likely to account for the different efficacies of full and partial 5-HT3, receptor agonists.
van Hooft
J A
JA
Research Institute of Toxicology, Utrecht University, Netherlands.
Vijverberg
H P
HP
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011985:Receptors, Serotonin / Q000737:chemistry / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D012701:Serotonin