Disease relevance of KCNJ1

• RECENT FINDINGS: Previously, three genes (SLC12A2, the sodium-potassium-chloride co-transporter; KCNJ1, the ROMK potassium ion channel; ClC-Kb, the basolateral chloride ion channel) had been identified as causing antenatal and 'classic' Bartter syndrome [1].
• We report the identification of two heterozygous mutations of the gene for Kir 1.1 (ROMK) from an antenatal Bartter syndrome patient who presented at birth with mild salt wasting and a biochemical findings that mimicked primary pseudohypoaldosteronism type 1, such as hyperkalemia and hyponatremia, and evolved to a relatively benign course [2].
• These data demonstrate for the first time that a ROMK-type K(ATP) channel is present in salivary gland duct cells that is regulated by extracellular ATP and possibly by the cystic fibrosis transmembrane regulator [3].
• These results therefore indicate that histidine residues contribute to the sensitivity of the ROMK1 channel to hypercapnia and intracellular acidosis [4].
• Hypokalemia was less severe in the ROMK patients compared with the NKCC2 patients [5].

High impact information on KCNJ1

• Our findings establish the genetic heterogeneity of Bartter's syndrome, and demonstrate the physiologic role of ROMK in vivo [6].
• We have used biochemical and electrophysiological methods to identify regions required for homotypic interactions and those responsible for the incompatibility between IRK1 and two other members of the same subfamily (IRK2 and IRK3) and two members from other subfamilies (ROMK1 and 6.1 uK(ATP)) [7].
• We found that a single amino-acid change within the putative transmembrane domain M2, aspartate (D) in IRK1 to the corresponding asparagine (N) in ROMK1, controls the gating phenotype [8].
• A low-K intake stimulates PTK activity, which leads to increase in phosphorylation of cloned inwardly rectifying renal K (ROMK) channels, whereas a high-K intake has the opposite effect [9].
• Here, we report that long WNK1 inhibited ROMK1 by stimulating its endocytosis [10].

Chemical compound and disease context of KCNJ1

• Mutations in the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) and ATP-sensitive inwardly rectifying potassium channel (ROMK) of the thick ascending limb of Henle's loop have been identified in the antenatal Bartter syndrome [2].
• The incubation of cells in a medium containing tetanus toxin abolished the herbimycin A-induced increase in the number of surface ROMK1 [11].
• Two genes, the gene encoding the furosemide-sensitive apical Na-K-2Cl cotransporter (NKCC2) and the gene encoding the luminal inwardly-rectifying potassium channel Kir 1.1 (ROMK), have been reported to cause the neonatal subtype of Bartter syndrome [12].

Biological context of KCNJ1

• Several candidate genes map to this region of the genome including a number of ion channel genes such as GRIK4, SCNB2, KCNJ5 and KCNJ1 [13].
• The nucleotide sequence of the genomic DNA including and spanning these exons (the KCNJ1 locus) was obtained directly from lambda and P1 clones (a total of 40 kb) [14].
• Nucleotide sequence analysis of the human KCNJ1 potassium channel locus [14].
• Dietary K(+) restriction decreases ROMK abundance in the renal cortical-collecting ducts by stimulating endocytosis, an adaptative response important for conservation of K(+) during K(+) deficiency [10].
• Genetic heterogeneity of hyperprostaglandin E syndrome has been demonstrated by identification of mutations in the SLC12A1 gene as well as in the KCNJ1 gene [15].

Anatomical context of KCNJ1

• The posttranscriptional expression of ROMK in the plasma membrane of cells is regulated by delivery of protein from endoplasmic reticulum (ER) to the cell surface and by retrieval by dynamin-dependent endocytic mechanisms in clathrin-coated pits [16].
• Phosphorylation-regulated endoplasmic reticulum retention signal in the renal outer-medullary K+ channel (ROMK) [16].
• Also, the Ba(2+)-sensitive K(+) current in oocytes injected with green fluorescent protein (GFP)-R1S4/201A was only 5% of that in oocytes injected with wild type GFP-ROMK1 [17].
• Human ROMK1A, -B, and -C transcripts were identified in kidney, whereas only human ROMK1A mRNA could be detected in pancreatic islets and other tissues in which human ROMK1 was expressed at low levels [18].
• In order to identify KATP channels from human brain, we performed a polymerase chain reaction (PCR) using human cerebral cortex mRNA and primers derived from the ROMK1 sequence, a cDNA clone encoding an ATP-regulated potassium channel, recently isolated from rat kidney [19].

Associations of KCNJ1 with chemical compounds

• RESULTS: Compound heterozygosity of the fetus in KCNJ1 (D74Y/P110L) confirmed the clinical diagnosis of HPS at 26 weeks of gestation [20].
• The renal outer-medullary K+ channel (ROMK; Kir1.1) mediates K+ secretion in the renal mammalian nephron that is critical to both sodium and potassium homeostasis [16].
• The S44 in the NH(2) terminus of ROMK1 can be phosphorylated by PKA and serum- and glucocorticoid-inducible kinase-1, and this process increases surface expression of functional channels [16].
• Furthermore, the biotin labeling technique confirmed that the membrane fraction of ROMK channels was almost absent in HEK293 cells transfected with either R1S4/201A or R1S4/183/201A [17].
• Phosphoamino acid analyses of the ROMK phosphoproteins revealed that phosphate was attached exclusively to serine residues [21].

Regulatory relationships of KCNJ1

• In the kidney, WNK4 regulates the balance between NaCl reabsorption and K(+) secretion via variable inhibition of the thiazide-sensistive NaCl cotransporter and the K(+) channel ROMK [22].
• These studies show that WNK1 is able to suppress total current directly through ROMK by causing a marked reduction in its surface expression [23].
• However, additional co-expression studies in oocytes revealed WNK3 inhibited the renal-specific K+ channel ROMK1 activity greater than 5.5-fold (p < .0001) by altering its plasmalemmal surface expression; WNK3 did not affect ROMK1's conductance or open/closed probability [24].
• To determine whether SNARE proteins are involved in mediating exocytosis of ROMK1 induced by the inhibition of c-Src, we examined the effect of herbimycin A on ROMK1 trafficking in cells treated with tetanus toxin [11].
• We conclude that tyrosine dephosphorylation enhances the exocytosis of ROMK1 and that SNARE proteins are required for exocytosis induced by inhibition of PTK [11].

Other interactions of KCNJ1

• Glycosylation of GIRK1 at Asn119 and ROMK1 at Asn117 has different consequences in potassium channel function [25].
• The results of co-expressing WNK1 with ROMK in Xenopus oocytes are reported for the first time [23].
• WNK4 mutations behave as a loss of function for the Na+-Cl- cotransporter and a gain of function when it comes to ROMK and claudins [26].
• As measured by antibody binding of external epitope-tagged forms of Kir 1.1 in intact cells, NHERF-1 or NHERF-2 coexpression increased cell surface expression of ROMK [27].
• Within the kidney, WNKs probably regulate the surface expression of several proteins involved in ion transport, including the sodium-chloride cotransporter (NCCT) and the potassium channel renal outer medullary potassium channel (ROMK), based on co-expression studies in Xenopus oocytes [28].

Analytical, diagnostic and therapeutic context of KCNJ1

• Site-directed mutagenesis of each of these sites or double mutation of any two sites showed that ROMK proteins retained the ability to be phosphorylated by PKA both in vivo and in vitro to a variable extent, while triple mutation of all three PKA sites abolished the phosphorylation induced by cAMP agonists in transfected cells [21].
• Incubation of the purified His-tagged ROMK1 protein with PKC and radiolabeled ATP resulted in (32)P incorporation into ROMK1 detected by autoradiography [17].
• The isolation of the human ROMK1 gene, localized to chromosome band 11q24 by fluorescence in situ hybridization, indicated that the different ROMK1 transcripts were generated by alternative splicing [18].
• The organization of the hKCNJ1 gene was determined by combining this sequence information with data obtained from primer extension and RT-PCR experiments [14].
• We have used atomic force microscopy to examine ROMK1-GST and the native ROMK1 polypeptide cleaved from GST [29].

References