An abundant, truncated human sulfonylurea receptor 1 splice variant has prodiabetic properties and impairs sulfonylurea action |
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Authors: | Diethart Schmid Michael Stolzlechner Albin Sorgner Caterina Bentele Alice Assinger Peter Chiba Thomas Moeslinger |
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Institution: | (1) Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria;(2) Institute of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria |
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Abstract: | 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 (KATP) 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 KATP 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 KATP-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. |
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