title: Altered expression of Ano1 variants in human diabetic gastroparesis.
abstract: Diabetes affects many organs including the stomach. Altered number and function of interstitial cells of Cajal (ICC), the gastrointestinal pacemaker cells, underlie a number of gastrointestinal motility disorders, including diabetic gastroparesis. In the muscle layers, ICC selectively express Ano1, thought to underlie classical Ca(2+)-activated Cl(-) currents. Mice homozygous for Ano1 knock-out exhibit abnormal ICC function and motility. Several transcripts for Ano1 are generated by alternative splicing of four exons. Here, we report expression levels of transcripts encoded by alternative splicing of Ano1 gene in gastric muscles of patients with diabetic gastroparesis and nondiabetic control tissues. Expression of mRNA from two alternatively transcribed exons are significantly different between patients and controls. Furthermore, patients with diabetic gastroparesis express mRNA for a previously unknown variant of Ano1. The 5' end of this novel variant lacks exons 1 and 2 and part of exon 3. Expression of this variant in HEK cells produces a decreased density of Ca(2+)-activated Cl(-) currents that exhibit slower kinetics compared with the full-length Ano1. These results identify important changes in expression and splicing of Ano1 in patients with diabetic gastroparesis that alter the electrophysiological properties of the channel. Changes in Ano1 expression in ICC may directly contribute to diabetic gastroparesis.
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Amelia
authors.initials: A
authors.lastname: Mazzone
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Bernard
authors.forename: Peter R
authors.initials: PR
authors.lastname: Strege
authors.forename: Arthur
authors.initials: A
authors.lastname: Beyder
authors.forename: Luis J V
authors.initials: LJ
authors.lastname: Galietta
authors.forename: Pankaj J
authors.initials: PJ
authors.lastname: Pasricha
authors.forename: James L
authors.initials: JL
authors.lastname: Rae
authors.forename: Henry P
authors.initials: HP
authors.lastname: Parkman
authors.forename: David R
authors.initials: DR
authors.lastname: Linden
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Szurszewski
authors.forename: Tamas
authors.initials: T
authors.lastname: Ördög
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Gibbons
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000075369:Anoctamin-1; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018589:Gastroparesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D056885:Interstitial Cells of Cajal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
chemical_list: C476213:ANO1 protein, human; C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D020033:Protein Isoforms