p38 MAP kinase modulates liver cell volume through inhibition of membrane Na+ permeability

Feranchak, Andrew P.; Berl, Tomás; Capasso, Juan M.; Wojtaszek, Paul A.; Han, Jiahuai; Fitz, John

doi:10.1172/jci200112190

Cited by 41 publications

(49 citation statements)

References 60 publications

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“…For example, in hepatocytes the basal activity of p38 MAP kinase is required for maintenance of cell volume through tonic inhibition of Na ϩ -permeable ion channels (30). In dendrites of pyramidal neurons, the basal activity of ERK1/2 is responsible for sustained downregulation of A-type outward potassium currents (31,32).…”

Section: Discussionmentioning

confidence: 99%

ERK1/2 Controls Na,K-ATPase Activity and Transepithelial Sodium Transport in the Principal Cell of the Cortical Collecting Duct of the Mouse Kidney

Michlig

Mercier

Doucet

et al. 2004

Journal of Biological Chemistry

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The collecting duct of normal kidney exhibits significant activity of the MEK1/2-ERK1/2 pathway as shown in vivo by immunostaining of phosphorylated active ERK1/2 (pERK1/2). The MEK1/2-ERK1/2 pathway controls many different ion transports both in proximal and distal nephron, raising the question of whether this pathway is involved in the basal and/or hormone-dependent transepithelial sodium reabsorption in the principal cell of the cortical collecting duct (CCD), a process mediated by the apical epithelial sodium channel and the basolateral sodium pump (Na,K-ATPase). To answer this question we used ex vivo microdissected CCDs from normal mouse kidney or in vitro cultured mpkCCD cl4 principal cells. Significant basal levels of pERK1/2 were observed ex vivo and in vitro. Aldosterone and vasopressin, known to up-regulate sodium reabsorption in CCDs, did not change ERK1/2 activity either ex vivo or in vitro. Basal and aldosterone-or vasopressin-stimulated sodium transport was down-regulated by the MEK1/2 inhibitor PD98059, in parallel with a decrease in pERK1/2 in vitro. The activity of Na,K-ATPase but not that of epithelial sodium channel was inhibited by MEK1/2 inhibitors in both unstimulated and aldosterone-or vasopressin-stimulated CCDs in vitro. Cell surface biotinylation showed that intrinsic activity rather than cell surface expression of Na,K-ATPase was controlled by pERK1/2. PD98059 also significantly inhibited the activity of Na,K-ATPase ex vivo. Our data demonstrate that the ERK1/2 pathway controls Na,K-ATPase activity and transepithelial sodium transport in the principal cell and indicate that basal constitutive activity of the ERK1/2 pathway is a critical component of this control.The extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) 1 pathway, also known as p42 and p44 mitogen-activated protein (MAP) kinase pathway, plays a critical role in cellular responses to a wide variety of external stimuli including hormones, growth factors, and environmental stress (for review, see Refs. 1 and 2). The ERK1/2 pathway is a three-step kinase cascade in which ERK1/2 kinases are phosphorylated/ activated by two immediate upstream MAP kinases (MEK1 and MEK2 (MEK1/2)) that are in turn phosphorylated/activated by several MAP kinases (i.e. MOS, C-Raf, and B-Raf). Activated ERK1/2 (pERK1/2) phosphorylates various downstream effectors involved in differentiation, proliferation, apoptosis, survival, cellular metabolism, and ion transport. The MAP kinase cascade may also be constitutively activated independent of external stimuli or ligands. This basal activity is the result of the balance between positive and negative factors regulating MAP kinases activity; that is, phosphatases, subcellular localization, expression of scaffold proteins, and activity of other kinases. In the kidney, the ERK1/2 pathway is involved in the hormonal regulation of different apical and basolateral channels or transporters expressed along the nephron for maintaining the extracellular fluid homeostasis. In the proximal tubule the ERK...

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Section: Discussionmentioning

confidence: 99%

ERK1/2 Controls Na,K-ATPase Activity and Transepithelial Sodium Transport in the Principal Cell of the Cortical Collecting Duct of the Mouse Kidney

Michlig

Mercier

Doucet

et al. 2004

Journal of Biological Chemistry

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“…These cells express insulin receptors, ion channels, and signaling pathways similar to those found in primary rat hepatocytes (5,6,(21)(22)(23). Decreases in cell volume caused by exposure to hypertonic buffer or oxidative stress are followed by Na ϩ influx through opening of NSC channels in the plasma membrane (5,6). Cells were passaged at weekly intervals and maintained at 37°C, 5% CO 2 in HCO 3 Ϫ -containing minimal essential media (Invitrogen) supplemented with heat-inactivated fetal bovine serum (10%) and L-glutamine (2 mM).…”

Section: Methodsmentioning

confidence: 86%

“…Under basal conditions, membrane Na ϩ permeability is low because of tonic inhibition of channels by p38 mitogen-activated protein (MAP) 1 kinase, a human homologue of the Saccharomyces cerevisiae HOG-1 gene product essential for cellular osmoregulation (6). Decreases in cell volume stimulated by oxidative stress and/or hypertonic exposure initiate an adaptive response that leads within minutes to Na ϩ influx through opening of nonselective cation (NSC) channels (5,7).…”

Section: In Liver Cells the Influx Of Namentioning

confidence: 99%

“…The resulting movement of water into the cell contributes to the restoration of volume toward basal values, a general process referred to as regulatory volume increase (RVI). Interestingly, hypertonic exposure has no effect on p38 MAP kinase activity, and the inhibitory effect of high intracellular concentrations of recombinant p38 MAP kinase can be overcome by changes in cell volume (6). Thus, it seems likely that inhibitory signaling is counterbalanced by additional, as yet unidentified pathways that increase the number or activity of NSC channels in the plasma membrane.…”

Section: In Liver Cells the Influx Of Namentioning

confidence: 99%

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Volume-sensitive Tyrosine Kinases Regulate Liver Cell Volume through Effects on Vesicular Trafficking and Membrane Na+ Permeability

Feranchak

Kilic

Wojtaszek

et al. 2003

Journal of Biological Chemistry

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In liver cells, the influx of Na؉ mediated by nonselective cation (NSC) channels in the plasma membrane contributes importantly to regulation of cell volume. Under basal conditions, channels are closed; but both physiologic (e.g. insulin) and pathologic (e.g. oxidative stress) stimuli that are known to stimulate tyrosine kinases are associated with large increases in membrane Na ؉ permeability to ϳ80 pA/pF or more. Consequently, the purpose of these studies was to evaluate whether volumesensitive tyrosine kinases mediate cell volume increases through effects on the activity or distribution of NSC channel proteins. In HTC hepatoma cells, decreases in cell volume evoked by hypertonic exposure increased total cellular tyrosine kinase activity ϳ20-fold. Moreover, hypertonic exposure (320 -400 mosM) was followed after a delay by NSC channel activation and partial recovery of cell volume toward basal values (regulatory volume increase (RVI)). The tyrosine kinase inhibitors genistein and erbstatin prevented both NSC channel activation and RVI. Similarly, hypertonic exposure resulted in an increase in p60 c-src activity, and intracellular dialysis with recombinant p60 c-src led to activation of NSC currents in the absence of an osmolar gradient. Utilizing FM1-43 fluorescence, exposure to hypertonic media caused a rapid increase in the rate of exocytosis of ϳ40% (p < 0.01), and genistein inhibited both exocytosis and channel activation. These findings indicate that volume-sensitive increases in p60 c-src and/or related tyrosine kinases play a key role in the regulation of membrane Na ؉ permeability, suggesting that increases in the NSC conductance may be mediated in part through rapid recruitment of a distinct pool of channelcontaining vesicles.

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“…ATP release was studied in HTC cells that have been used as a model for hepatocyte ATP release and purinergic signaling [24,34]. Exposure to hypotonic solution evoked a rapid increase in luminescence which was followed by a slow and gradual increase in luminescence that persisted for many minutes after the exposure.…”

Section: Discussionmentioning

confidence: 99%

Evidence for sustained ATP release from liver cells that is not mediated by vesicular exocytosis

Dolovcak

Waldrop

Xiao

et al. 2011

Purinergic Signalling

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Extracellular ATP regulates many important cellular functions in the liver by stimulating purinergic receptors. Recent studies have shown that rapid exocytosis of ATP-enriched vesicles contributes to ATP release from liver cells. However, this rapid ATP release is transient, and ceases in~30 s after the exposure to hypotonic solution. The purpose of these studies was to assess the role of vesicular exocytosis in sustained ATP release. An exposure to hypotonic solution evoked sustained ATP release that persisted for more than 15 min after the exposure. Using FM1-43 (N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino) styryl)pyridinium dibromide) fluorescence to measure exocytosis, we found that hypotonic solution stimulated a transient increase in FM1-43 fluorescence that lasted~2 min. Notably, the rate of FM1-43 fluorescence and the magnitude of ATP release were not correlated, indicating that vesicular exocytosis may not mediate sustained ATP release from liver cells. Interestingly, mefloquine potently inhibited sustained ATP release, but did not inhibit an increase in FM1-43 fluorescence evoked by hypotonic solution. Consistent with these findings, when exocytosis of ATP-enriched vesicles was specifically stimulated by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), mefloquine failed to inhibit ATP release evoked by NPPB. Thus, mefloquine can pharmacologically dissociate sustained ATP release and vesicular exocytosis. These results suggest that a distinct mefloquinesensitive membrane ATP transport may contribute to sustained ATP release from liver cells. This novel mechanism of membrane ATP transport may play an important role in the regulation of purinergic signaling in liver cells.

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p38 MAP kinase modulates liver cell volume through inhibition of membrane Na+ permeability

Cited by 41 publications

References 60 publications

ERK1/2 Controls Na,K-ATPase Activity and Transepithelial Sodium Transport in the Principal Cell of the Cortical Collecting Duct of the Mouse Kidney

ERK1/2 Controls Na,K-ATPase Activity and Transepithelial Sodium Transport in the Principal Cell of the Cortical Collecting Duct of the Mouse Kidney

Volume-sensitive Tyrosine Kinases Regulate Liver Cell Volume through Effects on Vesicular Trafficking and Membrane Na+ Permeability

Evidence for sustained ATP release from liver cells that is not mediated by vesicular exocytosis

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