A human 5-hydroxytryptamine receptor type 3AS (5-HT3R-AS) subunit has been cloned from an amygdala cDNA library. We report the nucleotide and predicted amino acid sequence of the human subunit, which possesses 85% and 84% amino acid sequence identity with mouse and rat 5-HT3R-AS subunits, respectively. Acting on Xenopus laevis oocytes injected with RNA transcripts of the clone, 5-HT and selective 5-HT3 receptor agonists elicited inwardly directed current responses that displayed desensitization. Such currents were blocked in a concentration-dependent manner by selective and nonselective 5-HT3 receptor antagonists but were unaffected by compounds acting at G protein-linked 5-HT receptors. A quantitative comparison of the pharmacological profiles of human and mouse recombinant 5-HT3R-AS receptor complexes revealed differences in the potencies of some antagonist or agonist compounds tested, the most dramatic example being (+)-tu-bocurarine, which demonstrated an ∼ 1800-fold discrepancy in antagonist potency. In view of the small number of sequence substitutions that occur between the human and mouse homo-logues of the 5-HT3R-AS in the extracellularly located aminoterminal domain, compounds such as (+)-tubocurarine, in conjunction with site-directed mutagenesis, may prove to be valuable in locating amino acid residues that contribute to the ligand binding site(s) of the 5-HT3 receptor. Also, when methodological differences are taken into account, the present study suggests that a homo-oligomeric assembly of human 5-HT3R-AS subunits can account for the distinctive ligand binding properties of human 5-HT3 receptors established in postmortem brain tissue.
|Number of pages||9|
|Publication status||Published - 1 Dec 1995|