Cloning, Characterization, and Chromosomal Localization of a Human 5‐HT₆ Serotonin Receptor

Abstract

We describe the cloning and characterization of a human 5‐HT6 serotonin 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‐HT6 cDNA encodes a 440‐amino‐acid polypeptide whose sequence diverges significantly from that published for the rat 5‐HT6 receptor. Resequencing of the rat cDNA revealed a sequencing error producing a frame shift within the open reading frame. The human 5‐HT6 amino acid sequence is 89% similar to the corrected rat sequence. The recombinant human 5‐HT6 receptor 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‐HT1Dα receptor, suggesting that these may be closely linked. Comparison of genomic and cDNA clones for the human 5‐HT6 receptor also reveals an RsaI restriction fragment length polymorphism within the coding region.

Potential clozapine target sites on peripheral hematopoietic cells and stromal cells of the bone marrow

“…32 In addition, primers were not designed within known polymorphic coding regions such as for the 5ht2a and 5ht6 receptors. 64,65 Given the existence of multiple isoforms of the a1a receptor, 66 primers that were specific for this subtype but did not pertain to a particular isoform were used. Amplification of cDNA for each receptor was undertaken using cDNA of human brain cortex, caudate nucleus or white blood cells as a positive control.…”

A Null Mutation of the Serotonin 6 Receptor Alters Acute Responses to Ethanol

“…This is the case for the 5-HT 6 R, a G-protein-coupled receptor that is positively linked to the adenylate cyclase second messenger system (Monsma et al, 1993;Ruat et al, 1993;Kohen et al, 1996;Branchek and Blackburn, 2000). Receptor expression in rats, guinea pigs, and humans appears CNS-limited and most prominent in the caudate-putamen, nucleus accumbens, and olfactory tubercle, with lesser expression in the hippocampus, cortex, and amygdala (Monsma et al, 1993;Ruat et al, 1993;Ward et al, 1995;Kohen et al, 1996;Roberts et al, 2002). Several classes of psychotropic drugs such as atypical antipsychotics, tricyclic antidepressants, and hallucinogens bind with high affinity to 5-HT 6 Rs (Monsma et al, 1993;Roth et al, 1994;Glatt et al, 1995).…”

Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders

“…High levels of both protein and mRNA expression have been found in the caudate-putamen of rat and pig brain (Monsma et al, 1993;Ruat et al, 1993a;Ward et al, 1995;Kohen et al, 1996;Yoshioka et al, 1998;Hirst et al, 2000) as well as in the caudate nucleus and putamen of human brain (Kohen et al, 1996;Hirst et al, 2003), thus demonstrating a similar distribution pattern for this receptor in the brains of these species. In contrast, only low levels of both 5-HT 6 receptor protein and mRNA have been found in the same brain areas of two different strains of mice (Hirst et al, 2003).…”

“…Finally, with regards to the last three 5-HT receptor families, only moderate-to-low concentrations of both receptor proteins and mRNA have been found in the SN and the GP of rat and human brain for the 5-HT 5A (Rees et al, 1994;Oliver et al, 2000), 5-HT 6 (Kohen et al, 1996;430 Gerard et al, 1997;Hamon et al, 1999;Roberts et al, 2002;Hirst et al, 2003) and 5-HT 7 (Ruat et al, 1993b;Martin-Cora and Pazos, 2004;Varnas et al, 2004) receptor subtypes.…”