Phosphatidylinositol 4,5-Bisphosphate (PIP2) Stimulates Epithelial Sodium Channel Activity in A6 Cells

Yue, Gang; Malik, Bela; Yue, Guichin; Eaton, Douglas C.

doi:10.1074/jbc.m108951200

Cited by 156 publications

(156 citation statements)

References 25 publications

(17 reference statements)

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“…In addition to ROMK1, ENaC is also regulated by cholesterol 34,35 and PI(4,5)P 2 . [36][37][38] However, unlike ROMK1 channels, ENaC appears to be localized in microvilli. 39 Therefore, investigating how cholesterol and PI(4,5)P 2 regulate ENaC in microvilli would serve as interesting topics for our future studies.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…When multiple channel events were observed in a patch, the total number of functional channels (N) in the patch was determined by observing the number of peaks detected on all point-amplitude histograms. NPo, the product of the number of channels and the open probability calculated as described previously (46), or the open probability (Po) itself, was used to measure the channel activity within a patch. Initial (3-4 min) single-channel records were normally used as the control.…”

Section: Methodsmentioning

confidence: 99%

An oxygen-sensitive mechanism in regulation of epithelial sodium channel

Wang¹,

Publicover

Gu³

2009

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

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Epithelial sodium channels (ENaCs) are of immense importance, controlling Na ؉ transport across epithelia and thus playing a central role in all aspects of fluid clearance as well as numerous other functions. Regulation of these channels is critical. Here, we show that haem, a regulator of Na ؉ transport, directly influences ENaC activity, decreasing channel-open probability (but not unitary conductance) in inside-out patches (but not outside-out). Conversely, exposure to the protein in the presence of NADPH and at normoxic O2 tension (requirements for activity of hemeoxygenase) increases channel activity. CO, a product of hemeoxygenase activity, activated ENaC in a manner similar to that of haem plus NADPH. However, under hypoxic conditions, inhibition of ENaC by haem occurred even in the presence of NADPH. These data demonstrate a potent, O2-sensitive mechanism for regulation of ENaC, in which hemeoxygenase acts as the O2 sensor, its substrate and product inhibiting and stimulating (respectively) the activity of ENaC.CO ͉ ENaC ͉ haem ͉ HO ͉ haemoxygenase

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“…Elevated concentrations of inositol 1,4,5-trisphosphate mobilize intracellular calcium, whereas diacylglycerol directly activates protein kinase C isozymes; these bifurcating signals are necessary for many cellular responses, including cell proliferation and migration, smooth muscle contraction, platelet aggregation, and neurotransmission (4 -6). PIP 2 also directly regulates many cytosolic, cytoskeletal, and membrane proteins, and its depletion by phospholipase C isozymes regulates ion channel activity (7)(8)(9)(10)(11)(12).…”

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confidence: 99%

Membrane-induced Allosteric Control of Phospholipase C-β Isozymes

Charpentier

Waldo

Barrett

et al. 2014

Journal of Biological Chemistry

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Background: Phospholipase C-␤ (PLC-␤) isozymes hydrolyze phosphatidylinositol 4,5-bisphosphate to propagate signals for several physiological responses. Results: Membranes are essential for the allosteric release of autoinhibition of PLC-␤ isozymes. Conclusion: Activators of PLC-␤ release autoinhibition by orientating the isozymes at the membrane. Significance: The model described provides a better understanding of PLC-␤ regulation and potential mechanisms to inhibit their activation.

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Phosphatidylinositol 4,5-Bisphosphate (PIP2) Stimulates Epithelial Sodium Channel Activity in A6 Cells

Cited by 156 publications

References 25 publications

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

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

An oxygen-sensitive mechanism in regulation of epithelial sodium channel

Membrane-induced Allosteric Control of Phospholipase C-β Isozymes

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