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Gene Review

Abcc8  -  ATP-binding cassette, sub-family C...

Mus musculus

Synonyms: D930031B21Rik, SUR1, Sur
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Disease relevance of Abcc8

  • Whereas persistent hyperinsulinemic hypoglycemia of infancy underscores the importance of the K(ATP)-dependent ionic pathway in control of insulin release, the Sur1(-/-) animals provide a novel model for study of K(ATP)-independent pathways that regulate insulin secretion [1].
  • The hypersensitivity to ACh was reproduced in control islets by depolarization with the SUR1 inhibitor glyburide [2].
  • To complicate matters, isolated islets of SUR1-/- mice secrete little insulin in response to high glucose, which extrapolates to hyperglycemia in the intact animal [2].

High impact information on Abcc8

  • Our studies of ATP-sensitive K+ channel (K(ATP)) trafficking reveal an essential quality control function for a trafficking motif present in each of the alpha (Kir6.1/2) and beta (SUR1) subunits of the K(ATP) complex [3].
  • The structure, in combination with molecular modelling, suggests how SUR1 interacts with Kir6.2 [4].
  • The linker mutations also reduced (S1R) or abolished (S2R) MgATP-dependent activation of Kir6.2-R50G co-expressed with SUR1 or SUR2B [5].
  • Mutation of the conserved serine to arginine in the linker of NBD1 (S1R) or NBD2 (S2R) did not alter the ability of ATP or ADP (100 microM) to displace 8-azido-[(32)P]ATP binding to SUR1, or abolish ATP hydrolysis at NBD2 [5].
  • The therapeutically important K(+) channel openers (e.g. pinacidil, cromakalim, nicorandil) act specifically on the SUR2 muscle isoforms but, except for diazoxide, remain ineffective on the SUR1 neuronal/pancreatic isoform [6].

Chemical compound and disease context of Abcc8


Biological context of Abcc8

  • Thus, structural features in SUR1 required for proper channel function are distinct from those required for correct protein trafficking [8].
  • MATERIALS AND METHODS: Heterozygous Kir6.2(+/-) and SUR1(+/-) animals were generated by backcrossing from knockout animals [9].
  • CONCLUSIONS/INTERPRETATION: A significant proportion of Kir6.2 and SUR1 subunits reside on insulin-secretory vesicles and the distal secretory pathway in mouse beta cells but do not influence intravesicular ion homeostasis [10].
  • However, they overexpressed the SUR1 transgene, yielding a 9- to 12-fold increase in the density of [(3)H]glibenclamide binding to the cortex, hippocampus, and striatum [11].
  • We have cloned and characterized the promoter region of the mouse SUR1 gene, and have shown that it lacks CAAT and TATA boxes or an initiator element [12].

Anatomical context of Abcc8

  • RESULTS: SUR1 and Kir6.2 immunoreactivity were concentrated on dense-core vesicles and on vesicles plus the endoplasmic reticulum/Golgi network, respectively, in both islets and MIN6 cells [10].
  • These results indicate that the transgenic overexpression of SUR1 alone in forebrain structures significantly protects mice from seizures and neuronal damage without interfering with locomotor or cognitive function [11].
  • Studies of transcription initiation in several tissues showed that there is a common SUR1 promoter in brain, heart, and pancreas and in the pancreatic beta-cell line, betaTC3 [12].
  • [(3)H]glibenclamide binding to membranes from HEK293 cells transfected with SUR1 was displaced by NNC 55-9216 (IC(50) = 105 micromol/l), and this effect was impaired when NBD2 of SUR1 was replaced by that of SUR2A [13].
  • AIMS/HYPOTHESIS: Islets or beta cells from Sur1(-/-) mice were used to determine whether changes in plasma membrane potential (V(m)) remain coupled to changes in cytosolic Ca(2+) ([Ca(2+)](i)) in the absence of K(ATP) channels and thus provide a triggering signal for insulin secretion [14].

Associations of Abcc8 with chemical compounds

  • The F1388L-SUR1 channel has increased sensitivity to MgADP and metabolic inhibition, decreased sensitivity to glibenclamide, and responds to both diazoxide and pinacidil [8].
  • Sur1-Kir6.2 is the most common combination of K-ATP channel subunits in the brain and Kir6.2 plays an important role in glucose metabolism through pancreatic insulin secretion or hypothalamic glucose sensing [15].
  • These effects correlated with the presence of a small (0.13 nS) sulfonylurea-sensitive conductance in wild-type but not in SUR1-/- alpha-cells [16].
  • In alpha-cells isolated from SUR1-/- mice, both tolbutamide and glucose failed to produce membrane depolarization [16].
  • These results suggest NNC 55-9216 is a SUR1-selective PCO that requires structural determinants, which differ from those needed for activation of the K(ATP) channel by pinacidil and cromakalim [13].
  • Isolated islet perifusion studies demonstrated that exendin-(9-39) blocked amino acid-stimulated insulin secretion, which is abnormally increased in SUR-1(-/-) islets [17].

Regulatory relationships of Abcc8

  • Here we show evidence for the interaction of H+ with ATP in regulating a cloned K(ATP) channel, i.e. Kir6.2 expressed with and without the SUR1 subunit [18].
  • SUR1 subunits are strongly expressed at the sarcolemmal surface of ventricular myocytes (but not in the coronary vasculature), whereas SUR2 protein was found to be localized predominantly in cardiac myocytes and coronary vessels (mostly in smaller vessels) [19].

Other interactions of Abcc8

  • In contrast to wild-type, surviving dopaminergic SN neurons of homozygous weaver mouse exclusively expressed SUR1 + Kir6.2 during the active period of dopaminergic neurodegeneration [20].
  • In contrast to GABAergic neurons, single dopaminergic SN neurons displayed alternative co-expression of either SUR1, SUR2B or both SUR isoforms with Kir6 [20].
  • ATP-sensitive K+ channel-dependent regulation of glucagon release and electrical activity by glucose in wild-type and SUR1-/- mouse alpha-cells [16].
  • The results with galanin suggest that this peptide affects beta cells independently of K(ATP) currents and thus could contribute to the regulation of beta-cell function in SUR1(-/-) animals [21].
  • GLUT-1, GLUT-2, Kir6.2, and SUR1 expression was not significantly different between B1 and C3 cells, whereas E-cadherin was more abundantly expressed in B1 cells [22].

Analytical, diagnostic and therapeutic context of Abcc8


  1. Sur1 knockout mice. A model for K(ATP) channel-independent regulation of insulin secretion. Seghers, V., Nakazaki, M., DeMayo, F., Aguilar-Bryan, L., Bryan, J. J. Biol. Chem. (2000) [Pubmed]
  2. Restitution of defective glucose-stimulated insulin release of sulfonylurea type 1 receptor knockout mice by acetylcholine. Doliba, N.M., Qin, W., Vatamaniuk, M.Z., Li, C., Zelent, D., Najafi, H., Buettger, C.W., Collins, H.W., Carr, R.D., Magnuson, M.A., Matschinsky, F.M. Am. J. Physiol. Endocrinol. Metab. (2004) [Pubmed]
  3. A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane K(ATP) channels. Zerangue, N., Schwappach, B., Jan, Y.N., Jan, L.Y. Neuron (1999) [Pubmed]
  4. 3-D structural and functional characterization of the purified KATP channel complex Kir6.2-SUR1. Mikhailov, M.V., Campbell, J.D., de Wet, H., Shimomura, K., Zadek, B., Collins, R.F., Sansom, M.S., Ford, R.C., Ashcroft, F.M. EMBO J. (2005) [Pubmed]
  5. Mutations in the linker domain of NBD2 of SUR inhibit transduction but not nucleotide binding. Matsuo, M., Dabrowski, M., Ueda, K., Ashcroft, F.M. EMBO J. (2002) [Pubmed]
  6. The molecular basis of the specificity of action of K(ATP) channel openers. Moreau, C., Jacquet, H., Prost, A.L., D'hahan, N., Vivaudou, M. EMBO J. (2000) [Pubmed]
  7. Impaired glucagon secretory responses in mice lacking the type 1 sulfonylurea receptor. Shiota, C., Rocheleau, J.V., Shiota, M., Piston, D.W., Magnuson, M.A. Am. J. Physiol. Endocrinol. Metab. (2005) [Pubmed]
  8. Modulation of the trafficking efficiency and functional properties of ATP-sensitive potassium channels through a single amino acid in the sulfonylurea receptor. Cartier, E.A., Shen, S., Shyng, S.L. J. Biol. Chem. (2003) [Pubmed]
  9. Hyperinsulinism in mice with heterozygous loss of K(ATP) channels. Remedi, M.S., Rocheleau, J.V., Tong, A., Patton, B.L., McDaniel, M.L., Piston, D.W., Koster, J.C., Nichols, C.G. Diabetologia (2006) [Pubmed]
  10. Intracellular ATP-sensitive K(+) channels in mouse pancreatic beta cells: against a role in organelle cation homeostasis. Varadi, A., Grant, A., McCormack, M., Nicolson, T., Magistri, M., Mitchell, K.J., Halestrap, A.P., Yuan, H., Schwappach, B., Rutter, G.A. Diabetologia (2006) [Pubmed]
  11. Mice transgenically overexpressing sulfonylurea receptor 1 in forebrain resist seizure induction and excitotoxic neuron death. Hernández-Sánchez, C., Basile, A.S., Fedorova, I., Arima, H., Stannard, B., Fernandez, A.M., Ito, Y., LeRoith, D. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  12. Characterization of the mouse sulfonylurea receptor 1 promoter and its regulation. Hernández-Sánchez, C., Ito, Y., Ferrer, J., Reitman, M., LeRoith, D. J. Biol. Chem. (1999) [Pubmed]
  13. The novel diazoxide analog 3-isopropylamino-7-methoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide is a selective Kir6.2/SUR1 channel opener. Dabrowski, M., Ashcroft, F.M., Ashfield, R., Lebrun, P., Pirotte, B., Egebjerg, J., Bondo Hansen, J., Wahl, P. Diabetes (2002) [Pubmed]
  14. Crosstalk between membrane potential and cytosolic Ca2+ concentration in beta cells from Sur1-/- mice. Haspel, D., Krippeit-Drews, P., Aguilar-Bryan, L., Bryan, J., Drews, G., Düfer, M. Diabetologia (2005) [Pubmed]
  15. Cerebral glucose transporters expression and spatial learning in the K-ATP Kir6.2(-/-) knockout mice. Choeiri, C., Staines, W.A., Miki, T., Seino, S., Renaud, J.M., Teutenberg, K., Messier, C. Behav. Brain Res. (2006) [Pubmed]
  16. ATP-sensitive K+ channel-dependent regulation of glucagon release and electrical activity by glucose in wild-type and SUR1-/- mouse alpha-cells. Gromada, J., Ma, X., Høy, M., Bokvist, K., Salehi, A., Berggren, P.O., Rorsman, P. Diabetes (2004) [Pubmed]
  17. Exendin-(9-39) corrects fasting hypoglycemia in SUR-1-/- mice by lowering cAMP in pancreatic beta-cells and inhibiting insulin secretion. De León, D.D., Li, C., Delson, M.I., Matschinsky, F.M., Stanley, C.A., Stoffers, D.A. J. Biol. Chem. (2008) [Pubmed]
  18. Allosteric modulation of the mouse Kir6.2 channel by intracellular H+ and ATP. Wu, J., Cui, N., Piao, H., Wang, Y., Xu, H., Mao, J., Jiang, C. J. Physiol. (Lond.) (2002) [Pubmed]
  19. Immunolocalization of KATP channel subunits in mouse and rat cardiac myocytes and the coronary vasculature. Morrissey, A., Rosner, E., Lanning, J., Parachuru, L., Dhar Chowdhury, P., Han, S., Lopez, G., Tong, X., Yoshida, H., Nakamura, T.Y., Artman, M., Giblin, J.P., Tinker, A., Coetzee, W.A. BMC Physiol. (2005) [Pubmed]
  20. Alternative sulfonylurea receptor expression defines metabolic sensitivity of K-ATP channels in dopaminergic midbrain neurons. Liss, B., Bruns, R., Roeper, J. EMBO J. (1999) [Pubmed]
  21. Oscillations of membrane potential and cytosolic Ca(2+) concentration in SUR1(-/-) beta cells. Düfer, M., Haspel, D., Krippeit-Drews, P., Aguilar-Bryan, L., Bryan, J., Drews, G. Diabetologia (2004) [Pubmed]
  22. Differential gene expression in well-regulated and dysregulated pancreatic beta-cell (MIN6) sublines. Lilla, V., Webb, G., Rickenbach, K., Maturana, A., Steiner, D.F., Halban, P.A., Irminger, J.C. Endocrinology (2003) [Pubmed]
  23. Dynamic activation of K(ATP) channels in rhythmically active neurons. Haller, M., Mironov, S.L., Karschin, A., Richter, D.W. J. Physiol. (Lond.) (2001) [Pubmed]
  24. Transgenic overexpression of SUR1 in the heart suppresses sarcolemmal K(ATP). Flagg, T.P., Remedi, M.S., Masia, R., Gomes, J., McLerie, M., Lopatin, A.N., Nichols, C.G. J. Mol. Cell. Cardiol. (2005) [Pubmed]
  25. Ischemic preconditioning in the hippocampus of a knockout mouse lacking SUR1-based K(ATP) channels. Muñoz, A., Nakazaki, M., Goodman, J.C., Barrios, R., Onetti, C.G., Bryan, J., Aguilar-Bryan, L. Stroke (2003) [Pubmed]
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