Co-expression of the 5-HT3B serotonin receptor subunit alters the biophysics of the 5-HT3 receptor

Homomeric complexes of 5-HT(3A) receptor subunits form a ligand-gated ion channel. This assembly does not fully reproduce the biophysical and pharmacological properties of native 5-HT(3) receptors which might contain the recently cloned 5-HT(3B) receptor subunit. In the present study, heteromeric as...

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Bibliographic Details
Published in:Biophysical journal 2003-03, Vol.84 (3), p.1720-1733
Main Authors: Hapfelmeier, G, Tredt, C, Haseneder, R, Zieglgänsberger, W, Eisensamer, B, Rupprecht, R, Rammes, G
Format: Article
Language:English
Subjects:
Adaptation, Physiological
Cell Line
Channels, Receptors, and Transporters
Computer Simulation
Dose-Response Relationship, Drug
Humans
Ion Channel Gating - drug effects
Ion Channel Gating - physiology
Kidney - embryology
Kidney - metabolism
Membrane Potentials - drug effects
Membrane Potentials - physiology
Models, Biological
Receptors, Serotonin - chemistry
Receptors, Serotonin - classification
Receptors, Serotonin - drug effects
Receptors, Serotonin - metabolism
Receptors, Serotonin, 5-HT3
Recombinant Proteins - chemistry
Recombinant Proteins - classification
Recombinant Proteins - drug effects
Recombinant Proteins - metabolism
Serotonin - metabolism
Serotonin - pharmacology
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Summary:Homomeric complexes of 5-HT(3A) receptor subunits form a ligand-gated ion channel. This assembly does not fully reproduce the biophysical and pharmacological properties of native 5-HT(3) receptors which might contain the recently cloned 5-HT(3B) receptor subunit. In the present study, heteromeric assemblies containing human 5-HT(3A) and 5-HT(3B) subunits were expressed in HEK 293 cells to detail the functional diversity of 5-HT(3) receptors. We designed patch-clamp experiments with homomeric (5-HT(3A)) and heteromeric (5-HT(3AB)) receptors to emphasize the kinetics of channel activation and desensitization. Co-expression of the 5-HT(3B) receptor subunit reduced the sensitivity for 5-HT (5-HT(3A) receptor: EC(50) 3 micro M, Hill coefficient 1.8; 5-HT(3AB) receptor: EC(50) 25 micro M, 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-HT(3AB) receptor assemblies recovered much faster from desensitization than homomeric 5-HT(3A) receptor assemblies. Unexpectedly, the specific 5-HT(3) 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-HT(3) receptors in serotonergic transmission.
ISSN:0006-3495
1542-0086
DOI:10.1016/s0006-3495(03)74980-7