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

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Citation

Schmid D, Stolzlechner M, Sorgner A, Bentele C, Assinger A, Chiba P, Moeslinger T

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

Cell Mol Life Sci. 2012 Jan;69(1):129-48. doi: 10.1007/s00018-011-0739-x. Epub 2011 Jun 14.

PubMed ID
21671119 [ View in PubMed
]
Abstract

An alternatively spliced form of human sulfonylurea receptor (SUR) 1 mRNA lacking exon 2 (SUR1Delta2) 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 SUR1Delta2 and SUR1. The SUR1Delta2/(SUR1 + SUR1Delta2) 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 SUR1Delta2/SUR1/Kir6.2, the SUR1Delta2 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 SUR1Delta2, exhibited a strongly increased K(ATP) channel current upon transfection with SUR1Delta2. 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 SUR1Delta2 and slightly protected from non-insulin dependent diabetes in homozygotic individuals. Thus, SUR1Delta2 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.

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Polypeptides
NameUniProt ID
ATP-binding cassette sub-family C member 8Q09428Details