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* Department of Anaesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Department of Clinical Pharmacology, Max-Planck-Institute of Psychiatry, Munich, Germany; and Department of Psychiatry, Ludwig-Maximilians-Universität, Munich, Germany
Correspondence: Address reprint requests to Dr. Gerhard Hapfelmeier, Max-Planck-Institute of Psychiatry, Munich Kraepelinstr. 2-10, 80804 Munich, Germany. Tel.: +49-89-30622-255; Fax: +49-89-30622-402; E-mail: hapfelmeier{at}mpipsykl.mpg.de.
Homomeric complexes of 5-HT3A receptor subunits form a ligand-gated ion channel. This assembly does not fully reproduce the biophysical and pharmacological properties of native 5-HT3 receptors which might contain the recently cloned 5-HT3B receptor subunit. In the present study, heteromeric assemblies containing human 5-HT3A and 5-HT3B subunits were expressed in HEK 293 cells to detail the functional diversity of 5-HT3 receptors. We designed patch-clamp experiments with homomeric (5-HT3A) and heteromeric (5-HT3AB) receptors to emphasize the kinetics of channel activation and desensitization. Co-expression of the 5-HT3B receptor subunit reduced the sensitivity for 5-HT (5-HT3A receptor: EC50 3 µM, Hill coefficient 1.8; 5-HT3AB receptor: EC50 25 µM, Hill coefficient 0.9) and markedly altered receptor desensitization. Kinetic modeling suggested that homomeric receptors, but not heteromeric receptors, desensitize via an agonist-induced open-channel block. Furthermore, heteromeric 5-HT3AB receptor assemblies recovered much faster from desensitization than homomeric 5-HT3A receptor assemblies. Unexpectedly, the specific 5-HT3 receptor agonist mCPBG induced an open-channel block at both homomeric and heteromeric receptors. Because receptor desensitization and resensitization massively affect amplitude, duration, and frequency of synaptic signaling, these findings are evidence in favor of a pivotal role of subunit composition of 5-HT3 receptors in serotonergic transmission.
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