Abstract:We describe the cloning and characterization of a human 5‐HT6serotonin receptor. The open reading frame is interrupted by two introns in positions corresponding to the third cytoplasmic loop and the third extracellular loop. The human 5‐HT6cDNA encodes a 440‐amino‐acid polypeptide whose sequence diverges significantly from that published for the rat 5‐HT6receptor. Resequencing of the rat cDNA revealed a sequencing error producing a frame shift within the open reading frame. The human 5‐HT6amino acid sequence is 89% similar to the corrected rat sequence. The recombinant human 5‐HT6receptor is positively coupled to adenylyl cyclase and has pharmacological properties similar to the rat receptor with high affinity for several typical and atypical antipsychotics, including clozapine. The receptor is expressed in several human brain regions, most prominently in the caudate nucleus. The gene for the receptor maps to the human chromosome region 1p35–p36. This localization overlaps that established for the serotonin 5‐HT1Dαreceptor, suggesting that these may be closely linked. Comparison of genomic and cDNA clones for the human 5‐HT6receptor also reveals anRsaI restriction fragment length polymorphism with