The S-HT_3B subunit is a major determinant of serotonin-receptor function

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-HT_3A) 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)^2-7. Neuronal 5-HT₃ receptors also display a permeability to calcium ions and a current-voltage relationship that differ from those of homomeric receptors^3-5,8. Here we describe a new class of 5-HT₃-receptor subunit (5-HT_3B). Transcripts of this subunit are co-expressed with the 5-HT_3A subunit in the amygdala, caudate and hippocampus. Heteromeric assemblies of 5-HT_3A and 5-HT_3B 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-HT_3B 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-HT_3B subunit will be a valuable resource for defining the molecular mechanisms of ion-channel function.