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

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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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References

  1. Noma A (1983) ATP-regulated K+ channels in cardiac muscle. Nature 305:147–148

    Article  PubMed  CAS  Google Scholar 

  2. Venkatesh N, Lamp ST, Weiss JN (1991) Sulfonylureas, ATP-sensitive K+ channels, and cellular K+ loss during hypoxia, ischemia, and metabolic inhibition in mammalian ventricle. Circ Res 69(3):623–637

    PubMed  CAS  Google Scholar 

  3. Rorsman P (1997) The pancreatic beta-cell as a fuel sensor: an electrophysiologist’s viewpoint. Diabetologia 40(5):487–495

    Article  PubMed  CAS  Google Scholar 

  4. Seino S, Miki T (2003) Physiological and pathophysiological roles of ATP-sensitive K+ channels. Prog Biophys Mol Biol 81(2):133–176

    Article  PubMed  CAS  Google Scholar 

  5. Babenko AP, Aguilar Bryan L, Bryan J (1998) A view of sur/KIR6.X, KATP channels. Annu Rev Physiol 60:667–687

    Article  PubMed  CAS  Google Scholar 

  6. Bryan J, Munoz A, Zhang X, Dufer M, Drews G, Krippeit-Drews P, Aguilar-Bryan L (2007) ABCC8 and ABCC9: ABC transporters that regulate K+ channels. Pflugers Arch 453(5):703–718

    Article  PubMed  CAS  Google Scholar 

  7. Chutkow WA, Simon MC, Le Beau MM, Burant CF (1996) Cloning, tissue expression, and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular KATP channels. Diabetes 45(10):1439–1445

    Article  PubMed  CAS  Google Scholar 

  8. Chutkow WA, Makielski JC, Nelson DJ, Burant CF, Fan Z (1999) Alternative splicing of sur2 exon 17 regulates nucleotide sensitivity of the ATP-sensitive potassium channel. J Biol Chem 274(19):13656–13665

    Article  PubMed  CAS  Google Scholar 

  9. Gros L, Trapp S, Dabrowski M, Ashcroft FM, Bataille D, Blache P (2002) Characterization of two novel forms of the rat sulphonylurea receptor SUR1A2 and SUR1BDelta31. Br J Pharmacol 137(1):98–106

    Article  PubMed  CAS  Google Scholar 

  10. Hambrock A, Preisig-Muller R, Russ U, Piehl A, Hanley PJ, Ray J, Daut J, Quast U, Derst C (2002) Four novel splice variants of sulfonylurea receptor 1. Am J Physiol Cell Physiol 283(2):C587–C598

    PubMed  CAS  Google Scholar 

  11. Brady PA, Terzic A (1998) The sulfonylurea controversy: more questions from the heart. J Am Coll Cardiol 31(5):950–956

    Article  PubMed  CAS  Google Scholar 

  12. Ashfield R, Gribble FM, Ashcroft SJ, Ashcroft FM (1999) Identification of the high-affinity tolbutamide site on the SUR1 subunit of the K(ATP) channel. Diabetes 48(6):1341–1347

    Article  PubMed  CAS  Google Scholar 

  13. Elrod JW, Harrell M, Flagg TP, Gundewar S, Magnuson MA, Nichols CG, Coetzee WA, Lefer DJ (2008) Role of sulfonylurea receptor type 1 subunits of ATP-sensitive potassium channels in myocardial ischemia/reperfusion injury. Circulation 117(11):1405–1413

    Article  PubMed  CAS  Google Scholar 

  14. Gopalakrishnan M, Johnson DE, Janis RA, Triggle DJ (1991) Characterization of binding of the ATP-sensitive potassium channel ligand, [3H]glyburide, to neuronal and muscle preparations. J Pharmacol Exp Ther 257(3):1162–1171

    PubMed  CAS  Google Scholar 

  15. Hussain K, Cosgrove KE (2005) From congenital hyperinsulinism to diabetes mellitus: the role of pancreatic beta-cell KATP channels. Pediatr Diabetes 6(2):103–113

    Article  PubMed  Google Scholar 

  16. Huopio H, Reimann F, Ashfield R, Komulainen J, Lenko HL, Rahier J, Vauhkonen I, Kere J, Laakso M, Ashcroft F, Otonkoski T (2000) Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. J Clin Invest 106(7):897–906

    Article  PubMed  CAS  Google Scholar 

  17. Flanagan SE, Clauin S, Bellanne-Chantelot C, de Lonlay P, Harries LW, Gloyn AL, Ellard S (2009) Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat 30(2):170–180

    Article  PubMed  CAS  Google Scholar 

  18. Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch 391(2):85–100

    Article  PubMed  CAS  Google Scholar 

  19. Klapperstuck T, Glanz D, Klapperstuck M, Wohlrab J (2009) Methodological aspects of measuring absolute values of membrane potential in human cells by flow cytometry. Cytometry A 75(7):593–608

    PubMed  Google Scholar 

  20. Mittman S, Guo J, Agnew WS (1999) Structure and alternative splicing of the gene encoding alpha1G, a human brain T calcium channel alpha1 subunit. Neurosci Lett 274(3):143–146

    Article  PubMed  CAS  Google Scholar 

  21. Malboeuf CM, Isaacs SJ, Tran NH, Kim B (2001) Thermal effects on reverse transcription: improvement of accuracy and processivity in cDNA synthesis. Biotechniques 30(5):1074–1078 1080, 1082, passim

    PubMed  CAS  Google Scholar 

  22. Jones DT (1999) Protein secondary structure prediction based on position-specific scoring matrices. J Mol Biol 292(2):195–202

    Article  PubMed  CAS  Google Scholar 

  23. Wu C, Orozco C, Boyer J, Leglise M, Goodale J, Batalov S, Hodge CL, Haase J, Janes J, Huss JW 3rd, Su AI (2009) BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol 10(11):R130

    Article  PubMed  Google Scholar 

  24. Brunak S, Engelbrecht J, Knudsen S (1991) Prediction of human mRNA donor and acceptor sites from the DNA sequence. J Mol Biol 220(1):49–65

    Article  PubMed  CAS  Google Scholar 

  25. Hough E, Beech DJ, Sivaprasadarao A (2000) Identification of molecular regions responsible for the membrane trafficking of Kir6.2. Pflugers Arch 440(3):481–487

    Article  PubMed  CAS  Google Scholar 

  26. Gribble FM, Ashfield R, Ammala C, Ashcroft FM (1997) Properties of cloned ATP-sensitive K+ currents expressed in Xenopus oocytes. J Physiol 498(Pt 1):87–98

    PubMed  CAS  Google Scholar 

  27. Li L, Rojas A, Wu J, Jiang C (2004) Disruption of glucose sensing and insulin secretion by ribozyme Kir6.2-gene targeting in insulin-secreting cells. Endocrinology 145(9):4408–4414

    Article  PubMed  CAS  Google Scholar 

  28. Hussain M, Wareham AC (1994) Rundown and reactivation of ATP-sensitive potassium channels (KATP) in mouse skeletal muscle. J Membr Biol 141(3):257–265

    PubMed  CAS  Google Scholar 

  29. Ashfield R, Ashcroft SJ (1998) Cloning of the promoters for the beta-cell ATP-sensitive K-channel subunits Kir6.2 and SUR1. Diabetes 47(8):1274–1280

    Article  PubMed  CAS  Google Scholar 

  30. Curley M, Cairns MT, Friel AM, McMeel OM, Morrison JJ, Smith TJ (2002) Expression of mRNA transcripts for ATP-sensitive potassium channels in human myometrium. Mol Hum Reprod 8(10):941–945

    Article  PubMed  CAS  Google Scholar 

  31. Haynes JM, Cook AL (2006) Protein kinase G-induced activation of K(ATP) channels reduces contractility of human prostate tissue. Prostate 66(4):377–385

    Article  PubMed  CAS  Google Scholar 

  32. Acevedo JJ, Mendoza-Lujambio I, de la Vega-Beltran JL, Trevino CL, Felix R, Darszon A (2006) KATP channels in mouse spermatogenic cells and sperm, and their role in capacitation. Dev Biol 289(2):395–405

    Article  PubMed  CAS  Google Scholar 

  33. Bardou O, Trinh NT, Brochiero E (2009) Molecular diversity and function of K+ channels in airway and alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 296(2):145–155

    Google Scholar 

  34. Matlin AJ, Clark F, Smith CW (2005) Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol 6(5):386–398

    Article  PubMed  CAS  Google Scholar 

  35. Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR (2003) ESE finder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res 31(13):3568–3571

    Article  PubMed  CAS  Google Scholar 

  36. Sakamoto Y, Inoue H, Keshavarz P, Miyawaki K, Yamaguchi Y, Moritani M, Kunika K, Nakamura N, Yoshikawa T, Yasui N, Shiota H, Tanahashi T, Itakura M (2007) SNPs in the KCNJ11-ABCC8 gene locus are associated with type 2 diabetes and blood pressure levels in the Japanese population. J Hum Genet 52(10):781–793

    Article  PubMed  CAS  Google Scholar 

  37. Aittoniemi J, Fotinou C, Craig TJ, de Wet H, Proks P, Ashcroft FM (2009) Review. SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator. Philos Trans R Soc Lond B Biol Sci 364(1514):257–267

    Article  PubMed  CAS  Google Scholar 

  38. Winkler M, Stephan D, Bieger S, Kuhner P, Wolff F, Quast U (2007) Testing the bipartite model of the sulfonylurea receptor binding site: binding of A-, B-, and A + B-site ligands. J Pharmacol Exp Ther 322(2):701–708

    Article  PubMed  CAS  Google Scholar 

  39. Mikhailov MV, Mikhailova EA, Ashcroft SJ (2001) Molecular structure of the glibenclamide binding site of the beta-cell K(ATP) channel. FEBS Lett 499(1–2):154–160

    Article  PubMed  CAS  Google Scholar 

  40. Vila-Carriles WH, Zhao G, Bryan J (2007) Defining a binding pocket for sulfonylureas in ATP-sensitive potassium channels. Faseb J 21(1):18–25

    Article  PubMed  CAS  Google Scholar 

  41. Zerangue N, Schwappach B, Jan YN, Jan LY (1999) A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane K(ATP) channels. Neuron 22(3):537–548. doi:S0896-6273(00)80708-4[pii]

    Article  PubMed  CAS  Google Scholar 

  42. Chan KW, Zhang H, Logothetis DE (2003) N-terminal transmembrane domain of the SUR controls trafficking and gating of Kir6 channel subunits. EMBO J 22(15):3833–3843

    Article  PubMed  CAS  Google Scholar 

  43. Shyng S, Ferrigni T, Nichols CG (1997) Regulation of KATP channel activity by diazoxide and MgADP. Distinct functions of the two nucleotide binding folds of the sulfonylurea receptor. J Gen Physiol 110(6):643–654

    Article  PubMed  CAS  Google Scholar 

  44. Lepor NE (2004) Diabetes mellitus. The sulfonylurea controversy: friend or foe? Rev Cardiovasc Med 5(2):134–135

    PubMed  Google Scholar 

  45. Brady PA, Jovanovic A (2003) The sulfonylurea controversy: much ado about nothing or cause for concern? J Am Coll Cardiol 42(6):1022–1025

    Article  PubMed  Google Scholar 

  46. Suzuki M, Sasaki N, Miki T, Sakamoto N, Ohmoto-Sekine Y, Tamagawa M, Seino S, Marban E, Nakaya H (2002) Role of sarcolemmal K(ATP) channels in cardioprotection against ischemia/reperfusion injury in mice. J Clin Invest 109(4):509–516

    PubMed  CAS  Google Scholar 

  47. Jovanovic A, Jovanovic S, Lorenz E, Terzic A (1998) Recombinant cardiac ATP-sensitive K+ channel subunits confer resistance to chemical hypoxia-reoxygenation injury [see comments]. Circulation 98(15):1548–1555

    PubMed  CAS  Google Scholar 

  48. Dufer M, Haspel D, Krippeit-Drews P, Aguilar-Bryan L, Bryan J, Drews G (2009) Activation of the Na+/K+ -ATPase by insulin and glucose as a putative negative feedback mechanism in pancreatic beta-cells. Pflugers Arch 457(6):1351–1360

    Article  PubMed  CAS  Google Scholar 

  49. Bell DS, Mayo MS (1998) Improved glycemic control with use of oral hypoglycemic therapy with or without insulin. Endocr Pract 4(2):82–85

    PubMed  CAS  Google Scholar 

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Acknowledgments

Both Michael Stolzlechner and Albin Sorgner received a research grant from the Austrian Ministry of Science.

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Authors and Affiliations

  1. Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Diethart Schmid, Michael Stolzlechner, Albin Sorgner, Alice Assinger & Thomas Moeslinger

  2. Institute of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria

    Caterina Bentele & Peter Chiba

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  1. Diethart Schmid
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Correspondence to Diethart Schmid.

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Schmid, D., Stolzlechner, M., Sorgner, A. et al. An abundant, truncated human sulfonylurea receptor 1 splice variant has prodiabetic properties and impairs sulfonylurea action. Cell. Mol. Life Sci. 69, 129–148 (2012). https://doi.org/10.1007/s00018-011-0739-x

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