The pharmacological and functional characteristics of the serotonin 5-HT3A receptor are specifically modified by a 5-MT3B receptor subunit

While homomers containing 5-HT3A subunits form functional ligand-gated serotonin (5-HT) receptors in heterologous expression systems (Jackson, M. B., and Yakel, J. L. (1995) Annu. Rev. Physiol. 57, 447-468; Lambert, J. J., Peters, J. A., and Hope, A. G. (1995) in Ligand-Voltage-Gated Ion Channels (North, R., ed) pp. 177-211, CRC Press, Inc., Boca Raton, FL), it has been proposed that native receptors may exist as heteromers (Fletcher, S., and Barnes, N. M. (1998) Trends Pharmacol. Sci. 19, 212-215). We report the cloning of a subunit 5-HT3B with similar to 44% amino acid identity to 5-HT3A that specifically modified 5-HT3A receptor kinetics, voltage dependence, and pharmacology. Go-expression of 5-HT3B with 5-HT3A modified the duration of 5-HT3 receptor agonist-induced responses, linearized the current-voltage relationship, increased agonist and antagonist affinity, and reduced cooperativity between subunits. Reverse transcriptase-polymerase chain reaction in situ hybridization revealed co-localization of both 5-HT3B and 5-HT3A in a population of neurons in the amygdala, telencephalon, and entorhinal cortex. Furthermore, 5-HT3A and 5-HT3B mRNAs were expressed in spleen and intestine. Our data suggest that 5-HT3B might contribute to tissue-specific functional changes in 5-HT3-mediated signaling and/or modulation.