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The 5-HT3B subunit is a major determinant of serotonin-receptor function

Abstract

The neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) mediates rapid excitatory responses through ligand-gated channels (5-HT3 receptors). Recombinant expression of the only identified receptor subunit (5-HT3A) yields functional 5-HT3 receptors1. However, the conductance of these homomeric receptors (sub-picosiemens) is too small to be resolved directly, and contrasts with a robust channel conductance displayed by neuronal 5-HT3 receptors (9–17 pS)2,3,4,5,6,7. Neuronal 5-HT3 receptors also display a permeability to calcium ions and a current–voltage relationship that differ from those of homomeric receptors3,4,5,8. Here we describe a new class of 5-HT3-receptor subunit (5-HT3B). Transcripts of this subunit are co-expressed with the 5-HT3A subunit in the amygdala, caudate and hippocampus. Heteromeric assemblies of 5-HT3A and 5-HT3B subunits display a large single-channel conductance (16 pS), low permeability to calcium ions, and a current–voltage relationship which resembles that of characterized neuronal 5-HT3 channels. The heteromeric receptors also display distinctive pharmacological properties. Surprisingly, the M2 region of the 5-HT3B subunit lacks any of the structural features that are known to promote the conductance of related receptors. In addition to providing a new target for therapeutic agents, the 5-HT3B subunit will be a valuable resource for defining the molecular mechanisms of ion-channel function.

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Figure 1: Amino-acid sequence and expression pattern of the human 5-HT3B subunit.
Figure 2: The pharmacological and biophysical properties of homomeric and heteromeric 5-HT3 receptors.
Figure 3: Alignment of the M2 regions for subunits of the Torpedo californica nACh receptor (tAChRα–δ), human muscle nACh receptor (hAChRα–ɛ), human neuronal nACh receptors (hAChRα2–β4) and human 5-HT3 receptors (h5-HT3A,B).

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Acknowledgements

We thank G. A. Evans for release to GenBank of unfinished sequence data from chromosome 11q23.1. This work was supported by grants from the NIH (to E.F.K. and T.G.H.) and the Wellcome Trust (to J.J.L. and J.A.P.).

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Correspondence to Ewen F. Kirkness.

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Davies, P., Pistis, M., Hanna, M. et al. The 5-HT3B subunit is a major determinant of serotonin-receptor function. Nature 397, 359–363 (1999). https://doi.org/10.1038/16941

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