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

• Isoflurane activated a glibenclamide-sensitive current in HEK293 cells expressing Kir6.2/SUR2B channels.Conclusion and implications:Isoflurane activates K(ATP) channels in vascular smooth muscle cells and produces coronary vasodilation in mouse hearts [8].
• Point mutations of the second nucleotide-binding domains (NBD2) of SUR1 and SUR2B, which would prevent ADP binding or ATP hydrolysis, showed similar effects [9].
• Insertional mutagenesis of the Sur2 locus generated homozygous null (Sur2(-/-)) mice and heterozygote (Sur2(+/-)) mice that are viable and phenotypically similar to their wild-type littermates to 6 weeks of age despite, respectively, half or no SUR2 mRNA expression or channel activity in skeletal muscle or heart [1].
• Here we report the isolation of a rat homolog of mouse SUR2B (denoted rSUR2B) from a rat kidney cDNA library [10].
• The rSUR2B sequence contains a 4,635-bp open reading frame that encodes a 1,545-amino acid polypeptide, showing 67% shared identity with SUR1 (a pancreatic beta-cell isoform) and 98% with both SUR2A (a brain isoform) and SUR2B (a vascular smooth muscle isoform) [10].

Anatomical context of Abcc9

• [(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 [11].
• 5. Therefore, the K+ channel composed of SUR2B and Kir6.1 is not a classical ATP-sensitive K+ channel but closely resembles the nucleotide diphosphate-dependent K+ channel in vascular smooth muscle cells [12].
• 1. We analysed the K+ channel composed of the sulphonylurea receptor 2B (SUR2B) and an inwardly rectifying K+ channel subunit Kir6.1 coexpressed in a mammalian cell line, HEK293T, with the patch clamp technique [12].
• Enhanced susceptibility to resveratrol was not observed in pancreatic beta-cells from SUR1 knock-out mice or in cells expressing the isoform SUR2A or SUR2B or the mutant SUR1(M1289T) [13].
• At a multiplicity of infection (MOI) of 1, viruses containing CR3 replicated better in Sur2+/+ mouse embryonic fibroblasts (MEFs) than in Sur2-/- MEFs [14].

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].

References