Disease relevance of KCNJ8

• There was no consistent effect of weight reduction on SUR2B or Kir6.1 expression [1].
• In addition, the Kir6.1 null mouse is a model of Prinzmetal angina in humans [2].
• Kir6.1 knockout mice exhibit sudden cardiac death due to cardiac ischemia, indicating that Kir6.1 rather than Kir6.2 is critical in the regulation of vascular tone [3].
• Gene knockout of the KCNJ8-encoded Kir6.1 K(ATP) channel imparts fatal susceptibility to endotoxemia [4].
• Here, in a model of acute septic shock induced by endotoxin challenge with Escherichia coli lipopolysaccharide (LPS), knockout of the KCNJ8 gene encoding the vascular Kir6.1 K(ATP) channel pore predisposed to an early and profound survival disadvantage [4].

High impact information on KCNJ8

• The Kir6.1-containing K(+) channel is critical in the regulation of vascular tonus, especially in the coronary arteries, and its disruption may cause Prinzmetal angina [5].
• Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1 [5].
• The K(+) channel opener pinacidil did not induce K(+) currents in vascular smooth-muscle cells of Kir6.1-null mice, and there was no vasodilation response to pinacidil [5].
• We report here that mice lacking the gene encoding Kir6.1 (known as Kcnj8) have a high rate of sudden death associated with spontaneous ST elevation followed by atrioventricular block as seen on an electrocardiogram [5].
• Although Kir6.1 and Kir6.2 are highly homologous and both form functional K+ channels with sulfonylurea receptors, their unitary conductances measured with 150 mM extracellular K+ are approximately 35 and 80 pS, respectively [6].

Biological context of KCNJ8

• KCNJ8 was mapped to chromosome 12p11.23 using fluorescence in situ hybridization [7].
• Somatic cell-hybrid mapping and fluorescence in-situ hybridization (FISH) localize human KCNJ8 to the short arm of human chromosome 12, at 12p12 [8].
• 5. The kinetics of UDP-dependent activation were significantly different between Kir6.1 and Kir6 [9].
• 1. A human aorta cDNA library was screened at low stringency with a rat pancreatic Kir6.1 cDNA probe and a homologue of Kir6.1 (hKir6.1) was isolated and sequenced [10].
• The human gene encoding uKATP-1, designated KCNJ8, is approximately 9.7 kb in length and is composed of three exons [7].

Anatomical context of KCNJ8

• These findings, taken together with the electrophysiological results, suggest that K(ATP) channel in corporal smooth muscle cells is composed of heteromultimers of Kir6.1 and Kir6.2 with the ratio of 3 : 1 or 4 : 0 and SUR2B [11].
• K ATP channels of primary human coronary artery endothelial cells consist of a heteromultimeric complex of Kir6.1, Kir6.2, and SUR2B subunits [12].
• Recently, we have isolated a KATP channel cDNA (uKATP-1) that is expressed ubiquitously in rat tissues including pancreatic islets, pituitary, skeletal muscle, and heart [7].
• Our results indicate that the major K(ATP) channel expressed in human myometrium is composed of Kir6.1 and SUR2B, and that down-regulation of this channel may facilitate myometrial function during late pregnancy [13].
• ROMK1 and KAB-2 are characterized with a Walker type-A ATP-binding motif in their carboxyl termini, and may be involved in K+ transport in renal epithelial and brain glial cells. uKATP-1 and BIR form with sulfonylurea receptors, the so-called ATP-sensitive K+ channels [14].

Associations of KCNJ8 with chemical compounds

• Although pinacidil is a nonselective activator of expressed sK(ATP) channels, diazoxide did not open channels formed by Kir6.1/SUR2A, Kir6.2/SUR2A (known components of cardiac sK(ATP) channels) or Kir6.2/SUR2B [15].
• P-1075 activated all the K(ATP) channels, except Kir6.1/SUR1 channels [15].
• In whole cells, the recombinant vascular K(ATP) channel, Kir6.1/SUR2B, was inhibited by HMR 1883 and glibenclamide with IC(50) values of 5.3 and 0.043 microM, respectively [16].
• Tempol also abolished the stimulatory effect of 30 muM nicotine on Kir6.1 currents [17].
• This inward current was significantly inhibited by PNU-37883A and by a specific anti-Kir6.1 antibody [17].

Physical interactions of KCNJ8

• However, until now the existence of such heteromultimeric Kir6.1/Kir6.2 complexes has not been demonstrated for native K(ATP) channels [12].
• This discovery may help design specific agents to selectively modulate the function of Kir6.1/SUR1 channel complex and facilitate the understanding of the structure-function relationship of specific subtype of K(ATP) channels [18].

Other interactions of KCNJ8

• Our results demonstrate that mitoK(ATP) channels closely resemble Kir6.1/SUR1 sK(ATP) channels in their pharmacological profiles [15].
• 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) [19].
• Urocortin-mediated cardioprotection involves several mechanisms, including increased expression of Kir6.1 K(ATP) channels and HSP90, although other as yet poorly understood mechanisms have also been implicated [20].
• KV2.1, BKCa, KIR6.1, and TASK1 were all demonstrated at the protein level [21].

Analytical, diagnostic and therapeutic context of KCNJ8

• We are the first to show that K(ATP) channel in human corporal smooth muscle is composed of Kir6.1-Kir6.2 construct expressed with SUR2B by RT-PCR [11].
• Western blotting and immunoprecipitation assays demonstrated the presence of Kir6.1 protein in both HCAEC and HCASMC; however, Kir6.2 protein was only expressed in HCAEC [12].
• Interaction between Kir6.1 and Kir6.2 subunits was demonstrated by reciprocal co-immunoprecipitation of these two subunits in HCAEC [12].
• Confocal microscopy imaging demonstrated Kir6.1 and Kir6.2 subunits to co-localize at the cell surface membrane in HCAEC [12].
• 1. Using the whole-cell patch-clamp technique, we investigated the interaction of nicotine with the Kir6.1 subunit as well as the underlying mechanism [17].

References