ROMK inwardly rectifying ATP-sensitive K+ channel. II. Cloning and distribution of alternative forms

Boim, Mirian Aparecida; Ho, Kevin; Shuck, Mary E.; Bienkowski, Michael J.; Block, Jennifer; Slightom, Jerry L.; Yang, Yanmin; Brenner, Barry M.; Hebert, Steven C.

doi:10.1152/ajprenal.1995.268.6.f1132

Cited by 146 publications

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“…ROMK staining is in red, clearly distributed in the apical membrane of the TAL and shows no difference of IF staining intensity between WT and KO mice kidneys, consistent with the finding that ROMK1 is not expressed in the TAL (9). marized in Table 6.…”

Section: Figure 8 Romk Localization In Mtal Of Romk1supporting

confidence: 84%

“…In addition to the difference in NH 2 terminus, they are also differentially expressed along the nephron from the TAL to the OMCD. In the rat, ROMK1 is expressed in the CCD and OMCD, whereas ROMK2 is expressed along the distal nephron including mTAL, CTAL, DCT, and CCD; ROMK3 is expressed in mTAL, cTAL, and DCT (9). The OMCD cells appear to express only the ROMK1 transcript (9).…”

Section: Discussionmentioning

confidence: 98%

“…In addition, ROMK1 transcripts are found in the outer medullary collecting duct (OMCD) where ROMK1 may provide K ϩ recycling for the renal H,K-ATPase. In the CCD, the ROMK2 transcript is also expressed, whereas in the OMCD the only transcript is ROMK1 (9). There are no studies assessing relative or absolute quanti- …”

Section: Generation Of Romk1 Knock-out Mice Bymentioning

confidence: 99%

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Romk1 Knockout Mice Do Not Produce Bartter Phenotype but Exhibit Impaired K Excretion

Dong

Yan

et al. 2016

Journal of Biological Chemistry

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Romk knock-out mice show a similar phenotype to Bartter syndrome of salt wasting and dehydration due to reduced Na-K2Cl-cotransporter activity. At least three ROMK isoforms have been identified in the kidney; however, unique functions of any of the isoforms in nephron segments are still poorly understood. We have generated a mouse deficient only in Romk1 by selective deletion of the Romk1-specific first exon using an ES cell CreLoxP strategy and examined the renal phenotypes, ion transporter expression, ROMK channel activity, and localization under normal and high K intake. The renal outer medullary potassium channel (ROMK) 3 is an ATP-dependent potassium channel (Kir1.1) that forms apical K channels that play an important role in K ϩ recycling to support sodium and chloride absorption in the thick ascending limb (TAL), and in regulation of K ϩ secretion in the collecting duct (CD). Mutations in the ROMK channel cause Type II Bartter syndrome that presents with polyhydramnios and postnatal life threatening volume depletion caused by loss of salt reabsorbing capacity by the thick ascending limb (1). Romk knock-out mice, originally generated from Gary Shull's lab at the University of Cincinnati, exhibited the same phenotypes as the Bartter syndrome in humans (2). By using the Romk Bartter mouse model, we have further confirmed that ROMK forms both small conductance K ϩ channels (SK) and 70 pS K channels in apical membranes of the thick ascending limb and cortical collecting duct (3, 4). We have demonstrated: 1) absence of both SK activity and 70 pS K ϩ channels in apical membranes of thick ascending limb and cortical collecting duct in Romk knock-out mice; 2) Romk knock-out mice produced similar phenotypes to Bartter syndrome consisting of salt and water wasting due to reduced NKCC2 activity and expression (3, 5); 3) the salt and water wasting from the kidney is compensated by increased thiazide-sensitive NaCl transport expression and activity, distal tubule hypertrophy, elevated renin-Ang II, and aldosterone levels (6). 4) The reduced K ϩ secretion in Romk null mice is compensated by increased maxi-K channel activity in the collecting tubule (7).However, three ROMK isoforms (ROMK1, -2, and -3) have been identified in the rat kidney (8 -10), but unique functions of any of the ROMK isoforms in nephron segments are still poorly understood. ROMK1 is expressed in the distal and collecting tubules and uniquely regulated by PTK/PTP-dependent endocytosis, which may be the mechanism for high-K-mediated enhanced ROMK channel activity in the collecting tubule (11,12). To study the functional role of ROMK1 in the regulation of Na and K homeostasis, we have generated a mouse deficient only in Romk1 by selective deletion of the Romk1 exon, using an ES cell Cre-LoxP strategy. We have examined the phenotypes of these mice by metabolic and renal clearance, and examined K channel activities by the patch clamp. The ion transporters, Nkcc2, Ncc, and Romk2, expression were measured by Q-PCR and ROMK localization was examined by immun...

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Section: Figure 8 Romk Localization In Mtal Of Romk1supporting

confidence: 84%

Section: Discussionmentioning

confidence: 98%

Section: Generation Of Romk1 Knock-out Mice Bymentioning

confidence: 99%

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Romk1 Knockout Mice Do Not Produce Bartter Phenotype but Exhibit Impaired K Excretion

Dong

Yan

et al. 2016

Journal of Biological Chemistry

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“…In addition to regulation of ROMK channels in the CCD, two lines of evidence suggest that the ING4-MAPK pathway may also be involved in the regulation of K channels in the thick ascending limb (TAL): (i) ING4 is expressed in the TAL; and (ii) expression of ING4 inhibits ROMK2 channels known to be present in the TAL (29). ROMK channels are required for K recycling across the apical membrane in the TAL (30,31).…”

Section: Discussionmentioning

confidence: 99%

Inhibitor of growth 4 (ING4) is up-regulated by a low K intake and suppresses renal outer medullary K channels (ROMK) by MAPK stimulation

Zhang

Lin

Jin

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Dietary K intake plays an important role in the regulation of renal K secretion: a high K intake stimulates whereas low K intake suppresses renal K secretion. Our previous studies demonstrated that the Src family protein-tyrosine kinase and mitogen-activated protein kinase (MAPK) are involved in mediating the effect of low K intake on renal K channels and K secretion. However, the molecular mechanism by which low K intake stimulates MAPK is not completely understood. Here we show that inhibitor of growth 4 (ING4), a protein with a highly conserved plant homeodomain finger motif, is involved in mediating the effect of low K intake on MAPK. K restriction stimulates the expression of ING4 in the kidney and superoxide anions, and its related products are involved in mediating the effect of low K intake on ING4 expression. We used HEK293 cells to express ING4 and observed that expression of ING4 increased the phosphorylation of p38 and ERK MAPK, whereas down-regulation of ING4 with small interfering RNA decreased the phosphorylation of p38 and ERK. Immunocytochemistry showed that ING4 was expressed in the renal outer medullary potassium (ROMK)-positive tubules. Moreover, ING4 decreased K currents in Xenopus oocytes injected with ROMK channel cRNA. This inhibitory effect was reversed by blocking p38 and ERK MAPK. These data provide evidence for the role of ING4 in mediating the effect of low K intake on ROMK channel activity by stimulation of p38 and ERK MAPK.ERK ͉ hypokalemia ͉ p38 ͉ renal potassium metabolism ͉ superoxide I t is well known that low K intake suppresses renal K secretion by increasing K absorption and inhibiting K secretion (1, 2). The inhibitory effect of low K intake on renal K secretion is partially achieved by removing renal outer medullary potassium (ROMK)-like small conductance K channels from the apical membrane of principal cells in the cortical collecting duct (CCD) through a protein-tyrosine kinase (PTK)-dependent mechanism (3). We have demonstrated previously that low K intake stimulates the production of superoxide anions and its related products, which in turn increase PTK expression and activity (4, 5). Increased PTK activity stimulates tyrosine phosphorylation of ROMK channels and subsequently enhances the internalization of the ROMK channels (6, 7). Furthermore, we have shown that low K intake stimulates ERK and p38 MAPK, which inhibits ROMK channels by a PTKindependent pathway. However, the mechanism by which low K intake stimulates MAPK activity is not completely understood.Inhibitor of growth 4 (ING4) is a member of the ING family proteins. They have been shown to regulate cell cycle, transcription and oncogenesis (8), and to promote UV-induced apoptosis of skin cells (9). ING4 also plays an important role in inhibiting tumor growth and angiogenesis in brain tumor cells (10). Because K restriction causes renal hypertrophy (11) through stimulation of growth factor levels (12), it is possible that that ING family proteins may also be involved in mediating the effect of low K intake on...

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“…7,8 The ROMK1 channel in cortical collecting ducts (CCDs) has a small conductance; therefore, it is also termed the small conductance K + (SK) channel. 9 This channel may be responsible for drug-induced hyperkalemia, because cyclosporin A (CsA), an immunosuppressant drug that causes hyperkalemia, inhibits the channel.…”

mentioning

confidence: 99%

Lovastatin-Induced Phosphatidylinositol-4-Phosphate 5-Kinase Diffusion from Microvilli Stimulates ROMK Channels

Liu

Yang

et al. 2015

Journal of the American Society of Nephrology

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We recently showed that lovastatin attenuates cyclosporin A (CsA)-induced damage of cortical collecting duct (CCD) principal cells by reducing intracellular cholesterol. Previous studies showed that, in cell expression models or artificial membranes, exogenous cholesterol directly inhibits inward rectifier potassium channels, including Kir1.1 (Kcnj1; the gene locus for renal outer medullary K + [ROMK1] channels). Therefore, we hypothesized that lovastatin might stimulate ROMK1 by reducing cholesterol in CCD cells. Western blots showed that mpkCCD c14 cells express ROMK1 channels with molecular masses that approximate the molecular masses of ROMK1 in renal tubules detected before and after treatment with DTT. Confocal microscopy showed that ROMK1 channels were not in the microvilli, where cholesterolrich lipid rafts are located, but rather, the planar regions of the apical membrane of mpkCCD c14 cells. Furthermore, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P 2 ], an activator of ROMK channels, was detected mainly in the microvilli under resting conditions along with the kinase responsible for PI(4,5) P 2 synthesis, phosphatidylinositol-4-phosphate 5-kinase, type I g [PI(4)P5K I g], which may explain the low basal open probability and increased sensitivity to tetraethylammonium observed here for this channel. Notably, lovastatin induced PI(4)P5K I g diffusion into planar regions and elevated PI(4,5)P 2 and ROMK1 open probability in these regions through a cholesterol-associated mechanism. However, exogenous cholesterol alone did not induce these effects. These results suggest that lovastatin stimulates ROMK1 channels, at least in part, by inducing PI(4,5)P 2 synthesis in planar regions of the renal CCD cell apical membrane, suggesting that lovastatin could reduce cyclosporin-induced nephropathy and associated hyperkalemia.

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ROMK inwardly rectifying ATP-sensitive K+ channel. II. Cloning and distribution of alternative forms

Cited by 146 publications

References 0 publications

Romk1 Knockout Mice Do Not Produce Bartter Phenotype but Exhibit Impaired K Excretion

Romk1 Knockout Mice Do Not Produce Bartter Phenotype but Exhibit Impaired K Excretion

Inhibitor of growth 4 (ING4) is up-regulated by a low K intake and suppresses renal outer medullary K channels (ROMK) by MAPK stimulation

Lovastatin-Induced Phosphatidylinositol-4-Phosphate 5-Kinase Diffusion from Microvilli Stimulates ROMK Channels

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