Insulin stimulates NHE1 activity by sequential activation of phosphatidylinositol 3‐kinase and protein kinase C ζ in human erythrocytes

Sauvage, M.; Fathallah, Hassana; Giraud, Françoise

doi:10.1046/j.1432-1327.2000.01084.x

Cited by 76 publications

(71 citation statements)

References 46 publications

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“…52,53 Along these lines, the observation that established PI 3-K inhibitors such as wortmannin and LY294002 are able to inhibit PDGF-induced NHE1 activity confirms that PI 3-K is also involved in the regulation of NHE1 in human HSC after stimulation with PDGF. In keeping with this observation, the effect of canrenone on NHE1 activity could be ascribed to its inhibitory effect on PI 3-K activity.…”

Section: Discussionmentioning

confidence: 91%

“…Studies performed on different cell types have shown that activation of the NHE1 after stimulation with PDGF is dependent on the activation of different intracellular signaling pathways, including the Ras-mediated ERK cascade 48,50 and Ras-independent signaling cassettes such as the Nck-interacting kinase 51 and PI 3-K. 35 Particularly concerning PI 3-K involvement, activation of NHE1 by PDGF is blocked by preincubation with PI 3-K inhibitors, such as wortmannin, or by inhibition or down-regulation of protein kinase C. 35,52 More precisely, the isozyme of protein kinase C has been shown to be a downstream target of phosphatidylinositol 3,4,5-phosphate and to mediate the PI 3-K activation of NHE1. 52,53 Along these lines, the observation that established PI 3-K inhibitors such as wortmannin and LY294002 are able to inhibit PDGF-induced NHE1 activity confirms that PI 3-K is also involved in the regulation of NHE1 in human HSC after stimulation with PDGF.…”

Section: Discussionmentioning

confidence: 99%

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Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells

et al. 2003

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells

et al. 2003

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“…The effects of isoproterenol on insulin-stimulated glucose transport were mimicked by acidification and reversed by alkalinisation of the adipocytes, suggesting the effects of insulin are pH sensitive [24]. Insulin has been proposed to stimulate alkalinisation by stimulation of Na + /H + exchange in erythrocytes and myocytes [24,25]. However, Na + /H + exchange has been shown to be elevated in vascular smooth muscle cells derived from SHRSP [26], arguing against a role for reduced cell alkalinisation in aberrant insulin-stimulated GLUT4 translocation in adipocytes.…”

Section: Discussionmentioning

confidence: 99%

Reduced insulin-stimulated GLUT4 bioavailability in stroke-prone spontaneously hypertensive rats

et al. 2005

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Aims/hypothesis: Insulin-stimulated glucose transport is impaired in a genetic model of hypertension, the stroke-prone spontaneously hypertensive rat (SHRSP), yet the molecular mechanisms that underlie this defect in the animals remain unclear. Methods: We examined the effects of insulin on the trafficking of the insulin-responsive glucose transporter GLUT4 to the plasma membrane in isolated adipocytes from SHRSP and normotensive control WistarKyoto (WKY) rats. Results: Treatment of isolated adipocytes with insulin resulted in trafficking of GLUT4 to the plasma membrane. There was no significant difference in the magnitude of insulin-stimulated GLUT4 trafficking from intracellular membranes to the plasma membrane between strains. In contrast, we demonstrated that there is a significant reduction in GLUT4 accessible to the glucose photolabel Bio-LC-ATB-BGPA at the plasma membrane of SHRSP adipocytes compared with control rats. Conclusions/ interpretation: We propose that a large proportion of GLUT4 translocated to the plasma membrane in response to insulin is not able to bind substrate and catalyse transport in the SHRSP. Therefore, there is a reduction in bioavailable GLUT4 in SHRSP animals that is likely to account, at least in part, for the reduced insulin-stimulated glucose uptake.

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“…These include pertussis toxin-sensitive G protein ␣ subunits (45), G protein ␤␥ subunits (32), PKC (12)(13)(14), the Ras-mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase kinase pathway (7)(8)(9)(10), and Src family kinases (25). Although it has been shown that members of the Src family are volume-sensitive enzymes (11,16,17), our results do not support their role in the osmotic activation of NHE-1, which is in agreement with the study by Kapus et al (17).…”

Section: Discussionmentioning

confidence: 99%

“…These include mitogen-activated protein kinases such as extracellular signal-regulated protein kinase (ERK), stress-activated protein kinases (c-Jun N-terminal kinases) (7)(8)(9)(10), Src family tyrosine kinases p59 fgr and p56/59 hck (11), protein kinase C (12)(13)(14), Janus kinase (15), and phosphatidylinositol 3-kinase (13), although there is not a consensus that any of those kinases mediate hypertonicity-induced activation of NHE-1.…”

mentioning

confidence: 99%

Hypertonicity Activates Na+/H+ Exchange through Janus Kinase 2 and Calmodulin

Garnovskaya

Mukhin

Vlasova

et al. 2003

Journal of Biological Chemistry

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The type 1 sodium-hydrogen exchanger (NHE-1) is a ubiquitous electroneutral membrane transporter that is activated by hypertonicity in many cells. NHE-1 may be an important pathway for Na ؉ entry during volume restoration, yet the molecular mechanisms underlying the osmotic regulation of NHE-1 are poorly understood. In the present study we conducted a screen for important signaling molecules that could be involved in hypertonicity-induced activation of NHE-1 in CHO-K1 cells. Hypertonicity rapidly activated NHE-1 in a concentration-dependent manner as assessed by proton microphysiometry and by measurements of intracellular pH on a FLIPR TM (fluorometric imaging plate reader). Inhibitors of Ca 2؉ /calmodulin (CaM) and Janus kinase 2 (Jak2) attenuated this activation, whereas neither calcium chelation nor inhibitors of protein kinase C, the Ras-ERK1/2 pathway, Src kinase, and Ca 2؉ /calmodulindependent enzymes had significant effects. Hypertonicity also resulted in the rapid tyrosine phosphorylation of Jak2 and STAT3 (the major substrate of Jak2) and CaM. Phosphorylation of Jak2 and CaM were blocked by AG490, an inhibitor of Jak2. Immunoprecipitation studies showed that hypertonicity stimulates the assembly of a signaling complex that includes CaM, Jak2, and NHE-1. Formation of the complex could be blocked by AG490. Thus, we propose that hypertonicity induces activation of NHE-1 in CHO-K1 cells in large part through the following pathway: hypertonicity 3 Jak2 phosphorylation and activation 3 tyrosine phosphorylation of CaM 3 association of CaM with NHE-1 3 NHE-1 activation.The ubiquitous isoform of the Na ϩ /H ϩ exchanger (NHE-1) 1 is essential for the regulation of cellular volume and intracellular pH. NHE-1 is nearly quiescent in resting cells but is activated by a variety of hormones and growth factors (1, 2). NHE-1 is also rapidly activated by hypertonic stress in many cells (3), and this may be an important pathway for Na ϩ entry during volume restoration. Despite the potential importance of this process, the molecular mechanisms underlying the regulation of NHE-1 by hypertonicity have not been fully elucidated. The rapid activation of NHE-1 is often associated with an increase in its phosphorylation (3). Kinases that have been shown to directly phosphorylate NHE-1 include p90 S6 kinase (4) and the Nck-interacting kinase (5). However, deletion of the major phosphorylation sites contained within residues 636 -815 of NHE-1 only reduces its response to growth factors by about 50% (6), suggesting that mechanisms of regulation other than direct phosphorylation of NHE-1 are also important.Hypertonicity-induced shrinkage of mammalian cells is a powerful stimulant for many protein kinases that could play important direct or indirect roles in activating NHE-1. These include mitogen-activated protein kinases such as extracellular signal-regulated protein kinase (ERK), stress-activated protein kinases (c-Jun N-terminal kinases) (7-10), Src family tyrosine kinases p59 fgr and p56/59 hck (11), protein kinase C (12-14), Jan...

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Insulin stimulates NHE1 activity by sequential activation of phosphatidylinositol 3‐kinase and protein kinase C ζ in human erythrocytes

Cited by 76 publications

References 46 publications

Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells

Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells

Reduced insulin-stimulated GLUT4 bioavailability in stroke-prone spontaneously hypertensive rats

Hypertonicity Activates Na+/H+ Exchange through Janus Kinase 2 and Calmodulin

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