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Gene Review

ABCC9  -  ATP-binding cassette, sub-family C...

Homo sapiens

Synonyms: ABC37, ATFB12, ATP-binding cassette sub-family C member 9, CANTU, CMD1O, ...
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Disease relevance of ABCC9


High impact information on ABCC9

  • Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel [3].
  • C. elegans EOR-1/PLZF and EOR-2 positively regulate Ras and Wnt signaling and function redundantly with LIN-25 and the SUR-2 Mediator component [4].
  • K(ATP) channels contain a pore-forming inwardly rectifying potassium channel and a sulfonylurea receptor regulatory subunit (SUR1 or SUR2) [5].
  • In addition, SUR2 binds glibenclamide with lower affinity [6].
  • Coexpression of SUR2 and the inward rectifier K+ channel subunit Kir6.2 in COS1 cells reconstitutes the properties of K(ATP) channels described in cardiac and skeletal muscle [6].

Biological context of ABCC9

  • To investigate the role of SUR in apoptosis induction, we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either SUR1, the smooth muscular isoform SUR2B, or the mutant SUR1(M1289T) at which a single amino acid in transmembrane helix 17 (TM17) was exchanged by the corresponding amino acid of SUR2 [7].
  • Human SUR2 was localized to chromosome 12, p12.1 by fluorescent in situ hybridization [8].
  • DIAGNOSIS: K(ATP) channelopathy caused by missense mutation (Thr1547Ile) of the ABCC9 gene conferring predisposition to adrenergic AF originating from the vein of Marshall. MANAGEMENT: Disruption of arrhythmogenic gene-environment substrate at the vein of Marshall by radiofrequency ablation [9].
  • These data suggest that (a) phosphoinositides strongly compete with ATP at a binding site residing on Kir6.2; (b) electrostatic interaction is a characteristic property of this competition; and (c) in conjunction with SUR2, phosphoinositides render additional, complex effects on ATP inhibition [10].
  • Cell proliferation of human embryonic kidney cells (HEK 293) which endogenously express Kir6.1/SUR2 mRNA was stimulated by pinacidil in a dose-dependent manner, an effect that was partially abolished by glibenclamide (3 microM) [11].

Anatomical context of ABCC9


Associations of ABCC9 with chemical compounds

  • SUR1, the typical pancreatic SUR isoform, shows much higher affinity for glibenclamide but considerably lower affinity for most openers than SUR2 [15].
  • The SUR2 segment containing the 12th through 17th predicted transmembrane domains, TMD12-17, confers sensitivity to the benzopyran, cromakalim, and the pyridine, pinacidil, whereas an SUR1 segment which includes TMD6-11 and the first nucleotide-binding fold, NBF1, controls responsiveness to the benzothiadiazine, diazoxide [16].
  • Dissociation constants of sulfonylureas for SUR2A and SUR2B were 10- to 400-fold higher than for SUR1, however, amazingly the benzoic acid derivative meglitinide did not show lower affinity for SUR2 isoforms [17].
  • SUR2 subtype (A and B)-dependent differential activation of the cloned ATP-sensitive K+ channels by pinacidil and nicorandil [18].
  • It also highlights that small structural changes can dramatically shift the efficacy of the cyanoguanidine type of selective activators of Kir6.2/SUR2 potassium channels [19].

Other interactions of ABCC9

  • ABCC8 and ABCC9: ABC transporters that regulate K(+) channels [20].
  • In patch clamp experiments, the R-enantiomer (PNU-96293) inhibited Kir6.2/SUR2 channels (IC(50) approximately 50 nm in the whole cell configuration), whereas the S-enantiomer (PNU-96179) was a weak opener [21].
  • They also increased the levels of SUR2 and Kir6.2 (P<0.01), but had no effect on the level of Kir6.1 (P>0.05) [22].
  • This finding suggested that the hypertension could be caused by one or more of 3 genes, the ATP-dependent potassium channel Kir6.1, its regulator the sulfonyl urea receptor SUR2, and the phosphodiesterase PDE3A [23].

Analytical, diagnostic and therapeutic context of ABCC9


  1. A haplotype in the human Sur2 gene is associated with essential hypertension. Sato, N., Nakayama, T., Asai, S., Soma, M. Journal of human hypertension. (2006) [Pubmed]
  2. A novel Val734Ile variant in the ABCC9 gene associated with myocardial infarction. Minoretti, P., Falcone, C., Aldeghi, A., Olivieri, V., Mori, F., Emanuele, E., Calcagnino, M., Geroldi, D. Clin. Chim. Acta (2006) [Pubmed]
  3. ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Bienengraeber, M., Olson, T.M., Selivanov, V.A., Kathmann, E.C., O'Cochlain, F., Gao, F., Karger, A.B., Ballew, J.D., Hodgson, D.M., Zingman, L.V., Pang, Y.P., Alekseev, A.E., Terzic, A. Nat. Genet. (2004) [Pubmed]
  4. C. elegans EOR-1/PLZF and EOR-2 positively regulate Ras and Wnt signaling and function redundantly with LIN-25 and the SUR-2 Mediator component. Howard, R.M., Sundaram, M.V. Genes Dev. (2002) [Pubmed]
  5. Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K(ATP) channels. Chutkow, W.A., Pu, J., Wheeler, M.T., Wada, T., Makielski, J.C., Burant, C.F., McNally, E.M. J. Clin. Invest. (2002) [Pubmed]
  6. A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels. Inagaki, N., Gonoi, T., Clement, J.P., Wang, C.Z., Aguilar-Bryan, L., Bryan, J., Seino, S. Neuron (1996) [Pubmed]
  7. Glibenclamide-induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform SUR1 but not by expression of SUR2B or the mutant SUR1(M1289T). Hambrock, A., de Oliveira Franz, C.B., Hiller, S., Osswald, H. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  8. Cloning, tissue expression, and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular KATP channels. Chutkow, W.A., Simon, M.C., Le Beau, M.M., Burant, C.F. Diabetes (1996) [Pubmed]
  9. KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation. Olson, T.M., Alekseev, A.E., Moreau, C., Liu, X.K., Zingman, L.V., Miki, T., Seino, S., Asirvatham, S.J., Jahangir, A., Terzic, A. Nature clinical practice. Cardiovascular medicine (2007) [Pubmed]
  10. Phosphoinositides decrease ATP sensitivity of the cardiac ATP-sensitive K(+) channel. A molecular probe for the mechanism of ATP-sensitive inhibition. Fan, Z., Makielski, J.C. J. Gen. Physiol. (1999) [Pubmed]
  11. Developmental expression and functional significance of Kir channel subunits in ureteric bud and nephron epithelia. Braun, G.S., Veh, R.W., Segerer, S., Horster, M.F., Huber, S.M. Pflugers Arch. (2002) [Pubmed]
  12. Molecular characterization of a local sulfonylurea system in human adipose tissue. Gabrielsson, B.G., Karlsson, A.C., Lönn, M., Olofsson, L.E., Johansson, J.M., Torgerson, J.S., Sjöström, L., Carlsson, B., Edén, S., Carlsson, L.M. Mol. Cell. Biochem. (2004) [Pubmed]
  13. Novel and established potassium channel openers stimulate hair growth in vitro: implications for their modes of action in hair follicles. Davies, G.C., Thornton, M.J., Jenner, T.J., Chen, Y.J., Hansen, J.B., Carr, R.D., Randall, V.A. J. Invest. Dermatol. (2005) [Pubmed]
  14. Molecular characterization of human SUR2-containing K(ATP) channels. Davis-Taber, R., Choi, W., Feng, J., Hoogenboom, L., McNally, T., Kroeger, P., Shieh, C.C., Simmer, R., Brioni, J.D., Sullivan, J.P., Gopalakrishnan, M., Scott, V.E. Gene (2000) [Pubmed]
  15. Effect of two amino acids in TM17 of Sulfonylurea receptor SUR1 on the binding of ATP-sensitive K+ channel modulators. Hambrock, A., Kayar, T., Stumpp, D., Osswald, H. Diabetes (2004) [Pubmed]
  16. Pharmaco-topology of sulfonylurea receptors. Separate domains of the regulatory subunits of K(ATP) channel isoforms are required for selective interaction with K(+) channel openers. Babenko, A.P., Gonzalez, G., Bryan, J. J. Biol. Chem. (2000) [Pubmed]
  17. Stoichiometry of sulfonylurea-induced ATP-sensitive potassium channel closure. Dörschner, H., Brekardin, E., Uhde, I., Schwanstecher, C., Schwanstecher, M. Mol. Pharmacol. (1999) [Pubmed]
  18. SUR2 subtype (A and B)-dependent differential activation of the cloned ATP-sensitive K+ channels by pinacidil and nicorandil. Shindo, T., Yamada, M., Isomoto, S., Horio, Y., Kurachi, Y. Br. J. Pharmacol. (1998) [Pubmed]
  19. Arylcyanoguanidines as activators of Kir6.2/SUR1K ATP channels and inhibitors of insulin release. Tagmose, T.M., Schou, S.C., Mogensen, J.P., Nielsen, F.E., Arkhammar, P.O., Wahl, P., Hansen, B.S., Worsaae, A., Boonen, H.C., Antoine, M.H., Lebrun, P., Hansen, J.B. J. Med. Chem. (2004) [Pubmed]
  20. ABCC8 and ABCC9: ABC transporters that regulate K(+) channels. Bryan, J., Muñoz, A., Zhang, X., Düfer, M., Drews, G., Krippeit-Drews, P., Aguilar-Bryan, L. Pflugers Arch. (2007) [Pubmed]
  21. The stereoenantiomers of a pinacidil analog open or close cloned ATP-sensitive K+ channels. Lange, U., Löffler-Walz, C., Englert, H.C., Hambrock, A., Russ, U., Quast, U. J. Biol. Chem. (2002) [Pubmed]
  22. Pretreatment with fosinopril or valsartan reduces myocardial no-reflow after acute myocardial infarction and reperfusion. Zhao, J.L., Yang, Y.J., You, S.J., Jing, Z.C., Wu, Y.J., Cheng, J.L., Gao, R.L. Coron. Artery Dis. (2006) [Pubmed]
  23. Autosomal-dominant hypertension with type E brachydactyly is caused by rearrangement on the short arm of chromosome 12. Bähring, S., Rauch, A., Toka, O., Schroeder, C., Hesse, C., Siedler, H., Fesüs, G., Haefeli, W.E., Busjahn, A., Aydin, A., Neuenfeld, Y., Mühl, A., Toka, H.R., Gollasch, M., Jordan, J., Luft, F.C. Hypertension (2004) [Pubmed]
  24. A novel sulfonylurea receptor forms with BIR (Kir6.2) a smooth muscle type ATP-sensitive K+ channel. Isomoto, S., Kondo, C., Yamada, M., Matsumoto, S., Higashiguchi, O., Horio, Y., Matsuzawa, Y., Kurachi, Y. J. Biol. Chem. (1996) [Pubmed]
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