title: Comparison of 5-HT4 and 5-HT7 receptor expression and function in the circular muscle of the human colon.
abstract: Serotonin receptors are potential targets for treating functional bowel disorders. This study investigated the functional roles and expression of the 5-HT4 and the 5-HT7 receptor, which coexist in human colon circular smooth muscle. 5-HT3 receptor expression was also investigated. Part of the relaxant response to 5-HT was due to activation of 5-HT4 receptors as the apparent pKB value of the selective 5-HT4 antagonist, GR 113808, was 9.36. 5-HT4 mRNA levels were low in five tissues and undetectable in four others, but all responded to 5-HT with an EC50 value of 102.54+/-19.32 nM. The contribution of 5-HT7 receptors to the response was not readily demonstrated using the selective 5-HT7 antagonist, SB-269970, as its apparent pKB value of 7.19 (5-HT4 block with 1 microM GR 113808) was lower than the value obtained using the 5-HT7 guinea pig ileum assay (8.62). Nevertheless, the 5-HT7 receptor was expressed more consistently than the 5-HT4, but at similar levels. The 5-HT(3Ashort) and 5-HT(3B) subunits were co-expressed at similar levels, but the 5-HT(3Along) subunit was detected in only five of the nine samples tested. The findings show that 5-HT4-induced relaxation occurs at low to undetectable levels of tissue mRNA, as measured by qPCR. Although 5-HT7 receptor mRNA is detected at low, but consistent levels, the functional activity of this receptor is not readily identified given the currently available drugs.
authors.affiliation: Department of Pharmaceutical Biology, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Irving
authors.forename: Yean Y
authors.initials: YY
authors.lastname: Tan
authors.forename: Nathalie
authors.initials: N
authors.lastname: Tochon-Danguy
authors.forename: Haihuang
authors.initials: H
authors.lastname: Liu
authors.forename: Navinisha
authors.initials: N
authors.lastname: Chetty
authors.forename: Paul V
authors.initials: PV
authors.lastname: Desmond
authors.forename: Colin W
authors.initials: CW
authors.lastname: Pouton
authors.forename: Ian M
authors.initials: IM
authors.lastname: Coupar
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D003106:Colon / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010636:Phenols / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D007211:Indoles; D010636:Phenols; D012333:RNA, Messenger; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; C404922:SB 269970; D012702:Serotonin Antagonists; D013449:Sulfonamides; C104425:serotonin 7 receptor; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; C082871:GR 113808