Human 5-HT5 receptors:: the 5-HT5A receptor is functional but the 5-HT5B receptor was lost during mammalian evolution

We have isolated from a human genomic library the human 5-hydroxytryptamine 5-HT5A and 5-HT5B genes. The human 5-HT5A gene encodes a protein with similar characteristics to its mouse homologue. When expressed in monkey COS-7 cells, the human 5-HT5A receptor displayed a high affinity for tritiated 5-carbamidotryptamine ([H-3]5-CT; K-D = 2.8 nM) and iodinated lysergic acid diethylamide ([I-125]LSD; K-D = 187 pM). These binding sites displayed the following displacement profile: Ergotamine > Methiothepin > 5-CT, Ritanserin > 5-HT. Reverse transcriptase polymerase chain reaction (RT-PCR) experiments revealed the presence of human 5-HT5A mRNA in the central nervous system but not in peripheral organs. When expressed in Xenopus oocytes. the 5-HT5A receptor was able to couple to the inwardly rectifying K+ channel, GIRK(1). In contrast to the human 5-HT5A gene and the mouse 5-HT5B gene, the human 5-HT5B gene does not encode a functional protein because its coding sequence is interrupted by stop codons. Our results suggest. therefore, that the 5-HT5B receptor has been lost during evolution after the divergence between rodents and primates. The 5-HT5B receptor is the first example of a brain-specific protein that is absent in human, (C) 2001 Elsevier Science B.V. All rights reserved.