Disease relevance of Abcc8

• Mutations in the sulfonylurea receptor 1 (SUR1), a subunit of ATP-sensitive potassium (K(ATP)) channels, cause familial hyperinsulinism [1].
• Sulfonylurea receptor expression in rat brain: effect of chronic hypoxia during development [2].
• Direct photoaffinity labeling of the putative sulfonylurea receptor in rat beta-cell tumor membranes by [3H]glibenclamide [3].
• Co-expression in a baculovirus expression system of two parts of SUR1 between NBD1 and TM12 leads to restoration of glibenclamide binding activity, whereas expression of either individual N- or C-terminal part alone gave no glibenclamide binding activity, confirming a bivalent structure of the glibenclamide binding site [4].
• Glimepiride is a novel sulfonylurea drug for treatment of non-insulin-dependent diabetes mellitus with higher blood sugar lowering efficacy in diabetic patients than glibenclamide raising the question whether this characteristics is in line with different binding of glimepiride and glibenclamide to the beta-cell sulfonylurea receptor [5].
• Block of SUR1 with low-dose glibenclamide reduced cerebral edema, infarct volume and mortality by 50%, with the reduction in infarct volume being associated with cortical sparing [6].

High impact information on Abcc8

• RESULTS: Stimulation of cholangiocyte secretion by glibenclamide and tolbutamide required Cl - and was mediated by the sulfonylurea receptor 2B [7].
• To determine the interaction site(s) of ATP-sensitive K(+) (K(ATP)) channels for G-proteins, sulfonylurea receptor (SUR2A or SUR1) and pore-forming (Kir6.2) subunits were reconstituted in the mammalian cell line, COS-7 [8].
• This effect involved specific interactions between MgADP and SUR, as it required Mg(2+), but not ATP, and was abolished by point mutations in the second nucleotide-binding domain of SUR, which impaired channel activation by MgADP [9].
• The pharmacological phenotype of ATP-sensitive potassium (K(ATP)) channels is defined by their tissue-specific regulatory subunit, the sulfonylurea receptor (SUR), which associates with the pore-forming channel core, Kir6 [9].
• We have suggested that holo-mitoK(ATP) is a heteromultimer consisting of an inwardly rectifying K(+) channel (mitoKIR) and a sulfonylurea receptor (Grover, G. J., and Garlid, K. D. (2000) J. Mol. Cell. Cardiol. 32, 677-695) [10].

Chemical compound and disease context of Abcc8

• From these data, we conclude that sulfonylurea receptors develop mostly in the first 2 wk postnatally and chronic hypoxia increases sulfonylurea receptor expression in utero in spite of the fact that overall protein decreases [2].

Biological context of Abcc8

• The high-affinity sulfonylurea receptor: distribution, glycosylation, purification, and immunoprecipitation of two forms from endocrine and neuroendocrine cell lines [11].
• Denatonium did not displace glybenclamide from its binding sites on the sulfonylurea receptor (SUR) [12].
• The data suggest similar control of the sulfonylurea receptor from brain and pancreatic islets by protein phosphorylation [13].
• To investigate the possible role of alpha-endosulfine up-regulation in diabetes, we administered sulfonylureas, the exogenous ligands of SUR, to diabetic animals [14].
• Neither of the two protocols affected gene expression of the ion channel-associated proteins Kir6.2, sulfonylurea receptor 1, voltage-dependent calcium channel-alpha1, or Kv2 [15].

Anatomical context of Abcc8

• Rat homolog of sulfonylurea receptor 2B determines glibenclamide sensitivity of ROMK2 in Xenopus laevis oocyte [16].
• The sulfonylurea receptor is present in membranes from a number of endocrine and neuroendocrine cell lines, including HIT-T15, RINm5f, alpha TC-6, AtT-20, and GH3 cells [11].
• Three subtypes of SUR have been cloned: pancreatic (SUR1), cardiac (SUR2A), and vascular smooth muscle (SUR2B) [17].
• Since the EC50 values are close to those reported for vascular smooth muscle (VSM) cells, the SUR subtype may be similar to that in VSM cells, and could form the functional K(ATP) channel in rat colonic smooth muscle cells [17].
• ATP-sensitive potassium channels (K(ATP)) are formed from four pore-forming Kir6.2 subunits complexed with four regulatory sulfonylurea receptor subunits (SUR1 in pancreatic beta-cells, SUR2A in heart) [18].

Associations of Abcc8 with chemical compounds

• ATP-regulated (K(ATP)) channels are formed by an inward rectifier pore-forming subunit (Kir) and a sulfonylurea (glibenclamide)-binding protein, a member of the ATP binding cassette family (sulfonylurea receptor (SUR) or cystic fibrosis transmembrane conductance regulator) [19].
• RT-PCR revealed that nicorandil increased the eNOS and SUR2 mRNA levels by 2.2- and 2.0-fold, respectively, (p < 0.01 versus control), and that these increases were completely inhibited by glibenclamide [20].
• The modification, which may reflect functional disconnection between SUR1 and Kir6.2, is prevented by ATP and PIP2, which may act cooperatively to stabilize membrane cytoskeletons (F-actin structures) [21].
• Oleoyl-CoA also impaired channel inhibition by ATP, increasing the Ki values for both Kir6.2/SUR1 and Kir6.2DeltaC36 currents by approximately 3-fold [22].
• The third transmembrane domain of SUR is found to be an important determinant of the response to cromakalim, which possibly harbors at least part of its binding site [23].

Other interactions of Abcc8

• K-ATP channels consist of two structurally different subunits: a pore-forming subunit of the Kir6.0-family (Kir6.1 or Kir6.2) and a sulfonylurea receptor (SUR1, SUR2, SUR2A, SUR2B) with regulatory activity [24].
• BACKGROUND: Previously, we showed the expression of a unique sulfonylurea receptor (SUR) and its putative endogenous ligand, alpha-endosulfine, in mesangial cells and isolated glomeruli [14].

Analytical, diagnostic and therapeutic context of Abcc8

• Wild-type and chimeric SUR were coexpressed with Kir6.2 in Xenopus oocytes, and we studied the resulting channels with the patch-clamp technique in the excised inside-out configuration [23].
• Membrane expression of KATP channel proteins, the pore-forming inward rectifier Kir6.2, and the regulatory sulfonylurea receptor SUR2A were assessed in APC and non-APC hearts by Western blotting [25].
• Photoaffinity labeling of submitochondrial particles with [125I]-glibenclamide revealed a single specifically labeled polypeptide band of 28 kDa by SDS-PAGE that is postulated to be (or to form a part of) the mitochondrial sulfonylurea receptor [26].

References