The 5-HT3B subunit confers spontaneous channel opening and altered ligand properties of the 5-HT3 receptor.
Current receptor theory suggests that there is an equilibrium between the inactive (R) and active (R*) conformations of ligand-gated ion channels and G protein-coupled receptors. The actions of ligands in both receptor types could be appropriately explained by this two-state model. Ligands such as agonists and antagonists affect receptor function by stabilizing one or both conformations. The 5-HT3 receptor is a member of the Cys-loop ligand-gated ion channel superfamily participating in synaptic transmission. Here we show that co-expression of the 5-HT3A and 5-HT3B receptor subunits in the human embryonic kidney (HEK) 293 cells results in a receptor that displays a low level of constitutive (or agonist-independent) activity. Furthermore, we also demonstrate that the properties of ligands can be modified by receptor composition. Whereas the 5-hydroxytryptamine (5-HT) analog 5-methoxyindole is a partial agonist at the 5-HT3A receptor, it becomes a "protean agonist" (functioning as an agonist and an inverse agonist at the same receptor) at the 5-HT3AB receptor (after the Greek god Proteus, who was able to change his shape and appearance at will). In addition, the 5-HT analog 5-hydroxyindole is a positive allosteric modulator for the liganded active (AR*) conformation of the 5-HT3A and 5-HT3AB receptors and a negative allosteric modulator for the spontaneously active (R*) conformation of the 5-HT3AB receptor, suggesting that the spontaneously active (R*) and liganded active (AR*) conformations are differentially modulated by 5-hydroxyindole. Thus, the incorporation of the 5-HT3B subunit leads to spontaneous channel opening and altered ligand properties.
Hu
Xiang-Qun
XQ
Department of Biomedical Sciences, College of Health Sciences, Marquette University, Milwaukee, Wisconsin 53201-1881, USA. xiangqun.hu@marquette.edu
Peoples
Robert W
RW
D002460:Cell Line; D002468:Cell Physiological Phenomena; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D008956:Models, Chemical; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D011487:Protein Conformation; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry* / Q000378:metabolism*; D014162:Transfection
D018076:DNA, Complementary; D007211:Indoles; D008024:Ligands; D044406:Receptors, Serotonin, 5-HT3; C487413:5-methoxyindole