The serotonin 3 (5-HT₃) receptor is a ligand gated ion channel unlike the other 5-HT receptors which are G protein coupled receptors. The functional 5-HT₃ receptor forms a pentamer of five symmetrically arranged subunits surrounding a central pore. The 5-HT(3A) subunit was first identified at a molecular level and can form functional homomers or heteromers with the 5-HT(3B) subunit. Recently, three new 5-HT₃ subunits have been discovered and these can also form functional heteromers with the 5-HT(3A) subunit. In addition, splice variants of the 5-HT₃ subunits have also been reported. These findings have markedly increased the complexity of the 5-HT₃ receptor and may form part of the explanation of unresolved differences between studies investigating 5-HT₃ receptor function in cell lines compared with native tissues. In this review we discuss the properties of the different subunits and their distribution to determine if they contribute to functional changes in the 5-HT₃ receptor. Several recent pharmacogenomic studies have revealed single nucleotide polymorphisms (SNPs) and other variations in the different 5-HT₃ receptor subunits that are associated with various clinical conditions. We discuss the implications of these findings with respect to drug design and tailored pharmacogenomic therapies.
Background/AimsSeveral disorders of the gastrointestinal tract are associated with abnormal serotonin (5-HT) signaling or metabolism where the 5-HT 3 and 5-HT 4 receptors are clinically relevant. The aim was to examine the distribution of 5-HT 3 , 5-HT 4 , and 5-HT 7 receptors in the normal human colon and how this is associated with receptor interacting chaperone 3, G protein coupled receptor kinases, and protein LIN-7 homologs to extend previous observations limited to the sigmoid colon or the upper intestine.
MethodsSamples from ascending, transverse, descending, and sigmoid human colon were dissected into 3 separate layers (mucosa, longitudinal, and circular muscles) and ileum samples were dissected into mucosa and muscle layers (n = 20). Complementary DNA was synthesized by reverse transcription from extracted RNA and expression was determined by quantitative or end point polymerase chain reaction.
ResultsThe 5-HT3 receptor subunits were found in all tissues throughout the colon and ileum. The A subunit was detected in all samples and the C subunit was expressed at similar levels while the B subunit was expressed at lower levels and less frequently. The 5-HT3 receptor E subunit was mainly found in the mucosa layers. All splice variants of the 5-HT4 and 5-HT7 receptors were expressed throughout the colon although the 5-HT4 receptor d, g, and i variants were expressed less often.
ConclusionsThe major differences in 5-HT receptor distribution within the human colon are in relation to the mucosa and muscular tissue layers where the 5-HT 3 receptor E subunit is predominantly found in the mucosal layer which may be of therapeutic relevance.
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