title: Transcriptional regulation of the human Na+/H+ exchanger NHE3 by serotonin in intestinal epithelial cells.
abstract: Serotonin (5-HT) decreases NHE2 and NHE3 activities under acute conditions in human intestinal epithelial cells. Here, we have investigated the effects of 5-HT on expression of the human NHE3 gene and the mechanisms underlying its transcriptional regulation in differentiated C2BBe1 cells. Treatment of the human intestinal epithelial cell line, C2BBe1, with 5-HT (20 microM) resulted in a significant decrease in NHE3 mRNA and protein expression. In transient transfection studies, 5-HT repressed the NHE3 promoter activity by approximately 55%. The repression of the NHE3 promoter activity in response to 5-HT was accompanied by reduced DNA-binding activity of transcription factors Sp1 and Sp3 to the NHE3 promoter without alteration in their nuclear levels. Pharmacological inhibitors of protein kinase C reversed the inhibitory effect of 5-HT on the promoter activity. Our data indicate that 5-HT suppresses the transcriptional activity of the NHE3 promoter and this effect may be mediated by PKCalpha and modulation of DNA-binding affinities of Sp1 and Sp3.
authors.affiliation: Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL 60612, USA.
authors.forename: Md Ruhul
authors.initials: MR
authors.lastname: Amin
authors.forename: Leda
authors.initials: L
authors.lastname: Ghannad
authors.forename: Ahmad
authors.initials: A
authors.lastname: Othman
authors.forename: Ravinder K
authors.initials: RK
authors.lastname: Gill
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Dudeja
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Ramaswamy
authors.forename: Jaleh
authors.initials: J
authors.lastname: Malakooti
mesh_terms: D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C000613385:SLC9A3 protein, human; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D012701:Serotonin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C