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Characterization of the Novel Human Serotonin Receptor Subunits 5-HT_3C,5-HT_3D, and 5-HT_3E

Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany (B.N., D.M., J.K., G.R.); Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany (J.W., S.C., H.B., M.G., M.B.); and Advanced Light Microscopy Facility and Cell Biology/Cell Biophysics Programme, European Molecular Biology Laboratory, Heidelberg, Germany (J.R.)

Within the family of serotonin receptors, the 5-hydroxytryptamine-3 (5-HT₃) receptor is the only ligand-gated ion channel. It is composed of five subunits, of which the 5-HT_3A and 5-HT_3B subunits are best characterized. Several studies, however, have reported on the functional diversity of native 5-HT₃ receptors, which cannot solely be explained on the basis of the 5-HT_3A and 5-HT_3B subunits. After our discovery of further putative 5-HT₃ serotonin receptor-encoding genes, HTR3C, HTR3D, and HTR3E, we investigated whether these novel candidates and the isoform 5-HT_3Ea are able to form functional 5-HT₃ receptor complexes. Using immunofluorescence and immunoprecipitation studies of heterologously expressed proteins, we found that each of the respective candidates coassembles with 5-HT_3A. To investigate whether the novel subunits modulate 5-HT₃ receptor function, we performed radioligand-binding assays and calcium-influx studies in human embryonic kidney 293 cells. Our experiments revealed that the 5-HT_3C,5-HT_3D, 5-HT_3E, and 5-HT_3Ea subunits alone cannot form functional receptors. Coexpression with 5-HT_3A, however, results in the formation of functional heteromeric complexes with different serotonin efficacies. Potencies of two agonists and antagonists were nearly identical with respect to homomeric 5-HT_3A and heteromeric complexes. However, 5-HT showed increased efficacy with respect to 5-HT_3A/D and 5-HT_3A/E receptors, which is consistent with the increased surface expression compared with 5-HT_3A receptors. In contrast, 5-HT_3A/C and 5-HT_3A/Ea receptors exhibited decreased 5-HT efficacy. These data show for the first time that the novel 5-HT₃ subunits are able to form heteromeric 5-HT₃ receptors, which exhibit quantitatively different functional properties compared with homomeric 5-HT_3A receptors.

Address correspondence to: Dr. Beate Niesler, Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. E-mail: beate.niesler{at}med.uni-heidelberg.de

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