Disease relevance of Kcnj1

• The inwardly rectifying K+ channel, Kir1.1 (ROMK) appears to form the pore of the channel, and mutations in Kir1.1 are responsible for Bartter syndrome [1].
• We have analyzed the transcriptional regulation of K(ATP) genes in rat kidney following transient renal ischemia.We observed that mRNA expression level was down-regulated for Kir1.1 and Kir4.1 potassium channels between 24 and 120 h after ischemia [2].
• These results suggest that overexpression of ROMK and BSC-1 in the thick ascending limb combined with a deficiency in renal formation of 20-HETE may predispose Dahl S rats fed a high-salt diet to Na+ retention and hypertension [3].
• Regulation of ROMK and channel-inducing factor (CHIF) in acute renal failure due to ischemic reperfusion injury [4].
• In the thick ascending limb of Henle's loop, a decrease in ROMK and BSC-1 could result in decreased reabsorption of NaCl, a finding associated with hypokalemia [5].

High impact information on Kcnj1

• Based on sequence homology with cloned inwardly rectifying K+ channels, ROMK1 (ref. 11) and IRK1 (ref. 12), we have isolated a complementary DNA for a G-protein-coupled inwardly rectifying K+ channel (GIRK1) from rat heart [6].
• 1. Reconstitution studies in Xenopus oocytes reveal that L-WNK1 significantly inhibits Kir1.1 by reducing cell surface localization of the channel [7].
• Acute dietary potassium loading increases the relative abundance of KS-WNK1 to L-WNK1 transcript and protein in the kidney, indicating that physiologic up-regulation of Kir1.1 activity involves a WNK1 isoform switch and KS-WNK1-mediated release from L-WNK1 inhibition [7].
• We have shown that maltose-binding fusion proteins (MBP) containing the COOH termini of K(ATP) channels (Kir1.1, Kir6.1, and Kir6.2) form functional tetramers that directly bind at least two ATP molecules with negative cooperativity [8].
• A role for head group charge was supported by polycations (neomycin, spermine, and polylysine) reversing the effect of PIP2 on TNP-ATP binding to the Kir1.1 channel COOH terminal fusion protein [8].

Chemical compound and disease context of Kcnj1

• The present study was undertaken to characterize the effects of renal ischemia and reperfusion on plasma potassium (K) and on the gene expression of channel-inducing factor (CHIF), a putative K channel regulator, and of ROMK, the distal nephron secretory K channel [4].

Biological context of Kcnj1

• Also, the tyrosine phosphorylation of ROMK is modulated by dietary K intake [9].
• Also, addition of c-Src and [(32)P]ATP phosphorylated the synthesized peptide corresponding to amino acid sequence 333-362 of the COOH terminus of ROMK1 [9].
• ROMK channels were found to acquire mature glycosylation in a serine 44 phosphorylation-dependent manner, consistent with a phosphorylation-dependent trafficking step within the endoplasmic reticulum/Golgi [10].
• Dietary potassium restriction stimulates endocytosis of ROMK channel in rat cortical collecting duct [11].
• Therefore, for the majority of ROMK mutations, disturbances in protein trafficking remained unclear [12].

Anatomical context of Kcnj1

• Our previous studies showed that co-expression of ROMK2, but not ROMK1 or ROMK3, with rat SUR2B in oocytes generated glibenclamide-sensitive K(+) currents [13].
• A phosphorylation-dependent export structure in ROMK (Kir 1.1) channel overrides an endoplasmic reticulum localization signal [10].
• In addition, two early inframe stop mutations could be rescued by aminoglycosides, resulting in full-length ROMK and correct trafficking to the plasma membrane in a subset of transfected cells [12].
• We found that ROMK abundance in kidney cortex and CCDs was reduced in rats fed a K+-restricted diet compared with rats fed the control K+ diet [11].
• METHODS: Mutated ROMK potassium channels were expressed in Xenopus oocytes and a human kidney cell line and analyzed by two electrode voltage clamp analysis, immunofluorescence, and Western blot analysis [12].

Associations of Kcnj1 with chemical compounds

• Moreover, c-Src and ROMK are coexpressed in the same nephron segment [14].
• Treatment of the CCD from rats on a HK diet with phenylarsine oxide (PAO) decreases the positive staining in the plasma/subapical membrane and increases the ROMK staining in the intracellular compartment [14].
• An amino acid triplet in the NH2 terminus of rat ROMK1 determines interaction with SUR2B [13].
• We constructed a series of hemagglutinin-tagged ROMK1 NH(2)-terminal deletion and substitution mutants and examined glibenclamide-sensitive K(+) currents in oocytes when co-expressed with SUR2B [13].
• These studies identified an amino acid triplet "IRA" within the conserved segment in the NH(2) terminus of ROMK1 and ROMK3 that blocks the ability of SUR2B to confer glibenclamide sensitivity to the expressed K(+) currents [13].

Regulatory relationships of Kcnj1

• We conclude that O(2)(-) and related products play a role in mediating the effect of low K intake on c-Src expression and in suppressing ROMK channel activity and renal K secretion [15].
• The selective adenosine A2a-receptor agonist CGS 21680 induced enhanced mRNA expression of both Kv1.3 and ROMK1, as well as an elevation of Kv1.3 protein [16].

Other interactions of Kcnj1

• Addition of active c-Src and [(32)P]ATP to the purified ROMK1 protein resulted in the phosphorylation of the ROMK1 protein [9].
• Aquaporin-2 and ROMK-1 proteins were detected in all three regions, but were moderately elevated (2-fold) only in the SHR inner medulla [17].

Analytical, diagnostic and therapeutic context of Kcnj1

• In vitro co-translation and immunoprecipitation studies with hemagglutinin-tagged ROMK mutants and SUR2B indicted that direct interaction between these two proteins is required for glibenclamide sensitivity of induced K(+) currents in oocytes [13].
• Using RT-PCR, we have identified a new set of ROMK isoforms in rat kidney that are generated by the deletion of a region within the ROMK core sequence that is identifiable as a typical mammalian intron [18].
• Using patch clamp techniques, we have investigated the regulation of ROMK1 with particular emphasis on phosphorylation/dephosphorylation processes [19].
• Using immunoblotting, a more than threefold increase in immunoreactive ROMK levels was observed in the outer medulla after dDAVP infusion [20].
• ROMK expression was reduced in the cortex and was completely abolished in the medulla at 48 to 72 hours of reperfusion [4].

References