An abundant, truncated human sulfonylurea receptor 1 splice variant has prodiabetic properties and impairs sulfonylurea action

• Published in: Cellular and molecular life sciences : CMLS 2012-01, Vol.69 (1), p.129-148
• Main Authors: Schmid, Diethart, Stolzlechner, Michael, Sorgner, Albin, Bentele, Caterina, Assinger, Alice, Chiba, Peter, Moeslinger, Thomas
• Format: Article
• Language: English
• Subjects: Alternative Splicing - physiology; Animals; ATP; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biochemistry; Biomedical and Life Sciences; Biomedicine; Calcium - metabolism; Cell Biology; Chlorocebus aethiops; COS Cells; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Exons - physiology; Glyburide - pharmacology; Humans; Hypoglycemic Agents - pharmacology; Insulin; Insulin - metabolism; Islets of Langerhans - metabolism; KATP Channels - drug effects; KATP Channels - metabolism; Life Sciences; Myocardium - metabolism; Neurons; Organ Specificity - genetics; Pancreas - metabolism; Polymorphism, Single Nucleotide; Potassium Channels, Inwardly Rectifying - genetics; Potassium Channels, Inwardly Rectifying - metabolism; Rats; Receptors, Drug - genetics; Receptors, Drug - metabolism; Relative abundance; Research Article; Ribonucleic acid; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Species Specificity; Sulfonylurea Receptors
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-011-0739-x

An alternatively spliced form of human sulfonylurea receptor (SUR) 1 mRNA lacking exon 2 (SUR1Δ2) has been identified. The omission of exon 2 caused a frame shift and an immediate stop codon in exon 3 leading to translation of a 5.6-kDa peptide that comprises the N-terminal extracellular domain and the first transmembrane helix of SUR1. Based on a weak first splice acceptor site in the human SUR1 gene (ABCC8), RT-PCR revealed a concurrent expression of SUR1Δ2 and SUR1. The SUR1Δ2/(SUR1 + SUR1Δ2) mRNA ratio differed between tissues, and was lowest in pancreas (46%), highest in heart (88%) and negatively correlated with alternative splice factor/splicing factor 2 (ASF/SF2) expression. In COS-7 cells triple transfected with SUR1Δ2/SUR1/Kir6.2, the SUR1Δ2 peptide co-immunoprecipitated with Kir6.2, thereby displacing two of four SUR1 subunits on the cell surface. The ATP sensitivity of these hybrid ATP-sensitive potassium channels (K ATP ) channels was reduced by about sixfold, as shown with single-channel recordings. RINm5f rat insulinoma cells, which genuinely express SUR1 but not SUR1Δ2, exhibited a strongly increased K ATP channel current upon transfection with SUR1Δ2. This led to inhibition of glucose-induced depolarization, calcium flux, insulin release and glibenclamide action. A non-mutagenic SNP on nucleotide position 333 (Pro69Pro) added another exonic splicing enhancer sequence detected by ASF/SF2, reduced relative abundance of SUR1Δ2 and slightly protected from non-insulin dependent diabetes in homozygotic individuals. Thus, SUR1Δ2 represents an endogenous K ATP -channel modulator with prodiabetic properties in islet cells. Its predominance in heart may explain why high-affinity sulfonylurea receptors are not found in human cardiac tissue.