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Gene Review

Abcc9  -  ATP-binding cassette, sub-family C...

Mus musculus

Synonyms: AI414027, AI449286, ATP-binding cassette sub-family C member 9, SUR2A, SUR2B, ...
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Disease relevance of Abcc9

  • Sur2(-/-) animals had lower fasting and fed serum glucose, exhibited improved glucose tolerance during a glucose tolerance test, and demonstrated a more rapid and severe hypoglycemia after administration of insulin [1].
  • Yet, diazoxide can be cardioprotective in ischemia and has been found to bind to the presumed cardiac sarcolemmal K(ATP) channel-regulatory subunit, SUR2A [2].
  • We have generated mice where the SUR2A was under the control of a cytomegalovirus promoter, a promoter that is more efficient than the native promoter [3].
  • We conclude that overexpression of SUR2A generates cardiac phenotype resistant to hypoxia/ischemia/reperfusion injury due at least in part to increase in levels of sarcolemmal K(ATP) channels [3].
  • To clarify the role of K(ATP) channels in vascular smooth muscle, we studied Sur2 gene-targeted mice (Sur2(-/-)) and found significantly elevated resting blood pressures and sudden death [4].

High impact information on Abcc9

  • Using in vivo monitoring, we detected transient, repeated episodes of coronary artery vasospasm in Sur2(-/-) mice [4].
  • The linker mutations also reduced (S1R) or abolished (S2R) MgATP-dependent activation of Kir6.2-R50G co-expressed with SUR1 or SUR2B [5].
  • These channels are heteromultimers composed of Kir6.2 subunit, an inwardly rectifying K(+) channel core, and SUR2A, a regulatory subunit implicated in ligand-dependent regulation of channel gating [6].
  • The finding that the major adenovirus E1A and mitogen-activated protein kinase-phosphorylated Elk1 activation domains bind to Sur2 uniquely among the metazoan mediator subunits and the development of transcriptionally active nuclear extracts from WT and sur2-/- embryonic stem cells, reported here, allowed a direct test of the model [7].
  • Disruption of Sur2-containing K(ATP) channels enhances insulin-stimulated glucose uptake in skeletal muscle [1].

Biological context of Abcc9


Anatomical context of Abcc9


Associations of Abcc9 with chemical compounds

  • The potency of glimepiride at the high-affinity site is close to that observed for glibenclamide (4 nM for SUR1, 27 nM for SUR2A), which has a similar structure [15].
  • A key role for the subunit SUR2B in the preferential activation of vascular K(ATP) channels by isoflurane [8].
  • SUR1, SUR2A, and SUR2B are sulfonylurea receptors that are characteristic for pancreatic, cardiac, and vascular smooth muscle-type K(ATP) channels, respectively [9].
  • It is therefore suggested that the C-terminal segment of SUR2A possesses an inhibitory effect on NBD2-mediated ADP-induced channel activation, which underlies the differential effects of ADP and diazoxide on K(ATP) channels containing different SURs [9].
  • Here, we have shown that the muscle form (M-LDH), but not heart form (H-LDH), of lactate dehydrogenase is directly physically associated with the sarcolemmal K(ATP) channel by interacting with the Kir6.2 subunit via its N-terminus and with the SUR2A subunit via its C-terminus [6].

Physical interactions of Abcc9

  • Taken together, the data indicate that HL-1 KATP channels are composed of sulfonylurea receptor isoform SUR2A coupled to the pore-forming Kir6.2 subunit--the molecular makeup of sarcKATP channels found in native cardiac myocytes [16].

Regulatory relationships of Abcc9

  • We find that SUR2B reaches the plasma membrane when coexpressed with Kir6.1 or Kir6.2 but not when coexpressed with Kir1.1b [17].
  • To examine this, we have generated transgenic (TG) mice that overexpress epitope-tagged SUR1 or SUR2A under the transcriptional control of the alpha-myosin heavy chain promoter [18].

Other interactions of Abcc9

  • In contrast to GABAergic neurons, single dopaminergic SN neurons displayed alternative co-expression of either SUR1, SUR2B or both SUR isoforms with Kir6 [19].
  • Kir6.2-SUR2A currents exhibited a single low-affinity site with a Ki of 0.8 +/- 0.1 mmol/l (n = 5), which is likely to reside on the Kir6.2 subunit [20].
  • Enhanced glucose use was also observed during in vivo hyperinsulinemic euglycemic clamp studies during which Sur2(-/-) mice required a greater glucose infusion rate to maintain a target blood glucose level [1].

Analytical, diagnostic and therapeutic context of Abcc9

  • However, at an MOI of 0.05, viruses lacking CR3 showed replication defects in Sur2-/- MEFs compared to Sur2+/+ MEFs, suggesting an E1A CR3 interaction-independent function of mSur2 in MAV-1 replication in cell culture [14].
  • Quantitative PCR showed that Kir 6.1 gene expression was upregulated by almost 22-fold, whereas SUR2B was downregulated by threefold after inflammation [21].
  • Western blot analysis showed that expression of Kir6.2 and SUR2A was similar between WT and CYP2J2 transgenic hearts [22].
  • In the present study, real-time RT-PCR has demonstrated that of all six sarcolemmal K(ATP) channel-forming proteins, SUR2A was probably the least expressed protein [3].
  • Kir6.2/SUR2A mediates the effects of K(ATP) channels openers on cardiac excitability and contractility and contributes to ischemic preconditioning [23].


  1. Disruption of Sur2-containing K(ATP) channels enhances insulin-stimulated glucose uptake in skeletal muscle. Chutkow, W.A., Samuel, V., Hansen, P.A., Pu, J., Valdivia, C.R., Makielski, J.C., Burant, C.F. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  2. Pharmacological plasticity of cardiac ATP-sensitive potassium channels toward diazoxide revealed by ADP. D'hahan, N., Moreau, C., Prost, A.L., Jacquet, H., Alekseev, A.E., Terzic, A., Vivaudou, M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  3. Overexpression of SUR2A generates a cardiac phenotype resistant to ischemia. Du, Q., Jovanović, S., Clelland, A., Sukhodub, A., Budas, G., Phelan, K., Murray-Tait, V., Malone, L., Jovanović, A. FASEB J. (2006) [Pubmed]
  4. 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]
  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. M-LDH serves as a sarcolemmal K(ATP) channel subunit essential for cell protection against ischemia. Crawford, R.M., Budas, G.R., Jovanović, S., Ranki, H.J., Wilson, T.J., Davies, A.M., Jovanović, A. EMBO J. (2002) [Pubmed]
  7. Activation domain-mediator interactions promote transcription preinitiation complex assembly on promoter DNA. Cantin, G.T., Stevens, J.L., Berk, A.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  8. A key role for the subunit SUR2B in the preferential activation of vascular K(ATP) channels by isoflurane. Fujita, H., Ogura, T., Tamagawa, M., Uemura, H., Sato, T., Ishida, A., Imamaki, M., Kimura, F., Miyazaki, M., Nakaya, H. Br. J. Pharmacol. (2006) [Pubmed]
  9. C-terminal tails of sulfonylurea receptors control ADP-induced activation and diazoxide modulation of ATP-sensitive K(+) channels. Matsuoka, T., Matsushita, K., Katayama, Y., Fujita, A., Inageda, K., Tanemoto, M., Inanobe, A., Yamashita, S., Matsuzawa, Y., Kurachi, Y. Circ. Res. (2000) [Pubmed]
  10. Rat homolog of sulfonylurea receptor 2B determines glibenclamide sensitivity of ROMK2 in Xenopus laevis oocyte. Tanemoto, M., Vanoye, C.G., Dong, K., Welch, R., Abe, T., Hebert, S.C., Xu, J.Z. Am. J. Physiol. Renal Physiol. (2000) [Pubmed]
  11. 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]
  12. Sulphonylurea receptor 2B and Kir6.1 form a sulphonylurea-sensitive but ATP-insensitive K+ channel. Yamada, M., Isomoto, S., Matsumoto, S., Kondo, C., Shindo, T., Horio, Y., Kurachi, Y. J. Physiol. (Lond.) (1997) [Pubmed]
  13. Resveratrol Binds to the Sulfonylurea Receptor (SUR) and Induces Apoptosis in a SUR Subtype-specific Manner. Hambrock, A., de Oliveira Franz, C.B., Hiller, S., Grenz, A., Ackermann, S., Schulze, D.U., Drews, G., Osswald, H. J. Biol. Chem. (2007) [Pubmed]
  14. E1A-CR3 interaction-dependent and -independent functions of mSur2 in viral replication of early region 1A mutants of mouse adenovirus type 1. Fang, L., Spindler, K.R. J. Virol. (2005) [Pubmed]
  15. Glimepiride block of cloned beta-cell, cardiac and smooth muscle K(ATP) channels. Song, D.K., Ashcroft, F.M. Br. J. Pharmacol. (2001) [Pubmed]
  16. Identification and pharmacological characterization of sarcolemmal ATP-sensitive potassium channels in the murine atrial HL-1 cell line. Fox, J.E., Jones, L., Light, P.E. J. Cardiovasc. Pharmacol. (2005) [Pubmed]
  17. Intrinsic sensitivity of Kir1.1 (ROMK) to glibenclamide in the absence of SUR2B. Implications for the identity of the renal ATP-regulated secretory K+ channel. Konstas, A.A., Dabrowski, M., Korbmacher, C., Tucker, S.J. J. Biol. Chem. (2002) [Pubmed]
  18. 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]
  19. 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]
  20. Differential sensitivity of beta-cell and extrapancreatic K(ATP) channels to gliclazide. Gribble, F.M., Ashcroft, F.M. Diabetologia (1999) [Pubmed]
  21. Altered gene expression and increased bursting activity of colonic smooth muscle ATP-sensitive K+ channels in experimental colitis. Jin, X., Malykhina, A.P., Lupu, F., Akbarali, H.I. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  22. Cardiac and vascular KATP channels in rats are activated by endogenous epoxyeicosatrienoic acids through different mechanisms. Lu, T., Ye, D., Wang, X., Seubert, J.M., Graves, J.P., Bradbury, J.A., Zeldin, D.C., Lee, H.C. J. Physiol. (Lond.) (2006) [Pubmed]
  23. Physiology and pathophysiology of K(ATP) channels in the pancreas and cardiovascular system: a review. Seino, S. J. Diabetes Complicat. (2003) [Pubmed]
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