The pharmacological and functional characteristics of the serotonin 5-HT(3A) receptor are specifically modified by a 5-HT(3B) receptor subunit.
While homomers containing 5-HT(3A) 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-HT(3B) with approximately 44% amino acid identity to 5-HT(3A) that specifically modified 5-HT(3A) receptor kinetics, voltage dependence, and pharmacology. Co-expression of 5-HT(3B) with 5-HT(3A) modified the duration of 5-HT(3) 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-HT(3B) and 5-HT(3A) in a population of neurons in the amygdala, telencephalon, and entorhinal cortex. Furthermore, 5-HT(3A) and 5-HT(3B) mRNAs were expressed in spleen and intestine. Our data suggest that 5-HT(3B) might contribute to tissue-specific functional changes in 5-HT(3)-mediated signaling and/or modulation.
Dubin
A E
AE
R. W. Johnson Pharmaceutical Research Institute, San Diego, California 92121, USA. audibin@prius.jnj.com
Huvar
R
R
D'Andrea
M R
MR
Pyati
J
J
Zhu
J Y
JY
Joy
K C
KC
Wilson
S J
SJ
Galindo
J E
JE
Glass
C A
CA
Luo
L
L
Jackson
M R
MR
Lovenberg
T W
TW
Erlander
M G
MG
D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001645:Biguanides / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D018728:Entorhinal Cortex / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007700:Kinetics; D046911:Macromolecular Substances; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D016366:Open Reading Frames; D011985:Receptors, Serotonin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D044406:Receptors, Serotonin, 5-HT3; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013687:Telencephalon / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014982:Xenopus laevis
D001645:Biguanides; D046911:Macromolecular Substances; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C065734:1-(3-chlorophenyl)biguanide; D002118:Calcium