The I1-imidazoline receptor in PC12 pheochromocytoma cells reverses NGF-induced ERK activation and induces MKP-2 phosphatase

Edwards, Lincoln; Ernsberger, Paul

doi:10.1016/s0006-8993(03)02893-2

Cited by 15 publications

(26 citation statements)

References 30 publications

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“…We chose LNP599 in this study because of its appropriate binding properties on I 1 R but also because it can cross the blood-brain barrier and has good intestinal absorption, permitting oral as well as intravenous delivery (Bousquet et al, 2011). Displacement of [ 125 I]PIC-specific binding by clonidine with high affinity confirmed that PC12 cell membranes represent a reference model for the study of I 1 R (Edwards and Ernsberger, 2003). The binding results demonstrated that LNP599 is a selective and specific molecule for I 1 R. Indeed, in PC12 cell membrane preparations, this molecule displaced the specific [ 125 I]PIC binding to I 1 R with nanomolar affinity and had no significant affinity for a large set of receptors, transporters, and enzymes, especially the different subtypes of b-adrenoceptors (see Supplemental Table) and of a 2 -adrenoceptors (Bousquet et al, 2011).…”

Section: Discussionmentioning

confidence: 64%

A New Pyrroline Compound Selective for I₁-Imidazoline Receptors Improves Metabolic Syndrome in Rats

Fellmann

Régnault

Greney

et al. 2013

J Pharmacol Exp Ther

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Symptoms of the metabolic syndrome (MetS), such as insulin resistance, obesity, and hypertension, have been associated with sympathetic hyperactivity. In addition, the adiponectin pathway has interesting therapeutic potentials in MetS. Our purpose was to investigate how targeting both the sympathetic nervous system and the adipose tissue (adiponectin secretion) with a drug selective for nonadrenergic I 1 -imidazoline receptors (I 1 Rs) may represent a new concept in MetS pharmacotherapy.125 I]para-iodoclonidine binding to I 1 R with nanomolar affinity and had no significant affinity for a large set of receptors, transporters, and enzymes. In addition, it can cross the blood-brain barrier and has good intestinal absorption, permitting oral as well as intravenous delivery. The presence of I 1 Rs was demonstrated in 3T3-L1 adipocytes; LNP599 had a specific stimulatory action on adiponectin secretion in adipocytes. Short-term administration of LNP599 (10 mg/kg i.v.) in anesthetized Sprague-Dawley rats markedly decreased sympathetic activity, causing hypotension and bradycardia. Long-term treatment of spontaneously hypertensive heart failure rats with LNP599 (20 mg/kg PO) had favorable effects on blood pressure, body weight, insulin resistance, glucose tolerance, and lipid profile, and it increased plasma adiponectin. The pyrroline derivative, which inhibits sympathetic activity and stimulates adiponectin secretion, has beneficial effects on all the MetS abnormalities. The use of one single drug with both actions may constitute an innovative strategy for the management of MetS.

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Section: Discussionmentioning

confidence: 64%

A New Pyrroline Compound Selective for I₁-Imidazoline Receptors Improves Metabolic Syndrome in Rats

Fellmann

Régnault

Greney

et al. 2013

J Pharmacol Exp Ther

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“…To test for a direct effect of moxonidine on Akt activation, we tested the effect of treatment with 100 nM moxonidine for 90 min. This concentration and duration of treatment has previously been shown to trigger multiple cell-signaling events in other cell types (Edwards et al, 2001;Edwards and Ernsberger, 2003). Akt activation in adipocytes treated with moxonidine alone was normalized to the control group treated with vehicle alone.…”

Section: Insulin Induced Glucose Uptake In Shr and Shrob Adipocytes Amentioning

confidence: 78%

Marked Insulin Resistance in Obese Spontaneously Hypertensive Rat Adipocytes Is Ameliorated by in Vivo but Not in Vitro Treatment with Moxonidine

Sun

Ernsberger

2006

J Pharmacol Exp Ther

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The obese spontaneously hypertensive rat (SHROB) is a model of marked insulin resistance with normoglycemia. We sought to determine whether insulin resistance extends to adipocytes and the impact of an insulin-sensitizing imidazoline, moxonidine (4 mg/kg/days for 21 days). Gonadal adipocytes were isolated from SHROB and lean spontaneously hypertensive rat (SHR) littermates. In lean SHR adipocytes, Akt activation by 100 nM insulin peaked at 3 min at 25-fold, whereas SHROB adipocytes showed only 4-fold activation. In dose-response experiments, the maximal response (E max ) was markedly reduced 18.8 Ϯ 2.3 versus 3.7 Ϯ 0.8. Insulin sensitivity was also attenuated, with higher concentrations required for responses (EC 50 ϭ 3.5 Ϯ 0.5 versus 29 Ϯ 3.8 nM). Glucose uptake as determined with [ 3 H]2-deoxyglucose was also less responsive to insulin in SHROB relative to lean SHR. Moxonidine had little or no effect when applied acutely in vitro, but adipocytes isolated from SHROB treated with moxonidine in vivo showed significantly improved responses to insulin, both in terms of Akt activation and facilitation of glucose uptake. Chronic but not acute moxonidine treatment partially restores insulin sensitivity in SHROB adipocytes, suggesting an indirect action of this agent.Obese spontaneously hypertensive rats (SHROB) are markedly insulin-resistant, showing a greater than 20-fold elevation fasting insulin levels in the presence of normal fasting glucose (Friedman et al., 1997;Velliquette et al., 2005). At the cellular level, defects in insulin action have been noted in skeletal muscle and the liver, as indicated by reduced insulin receptor protein, reduced levels of its substrate protein IRS-1, and impaired insulin-induced tyrosine phosphorylation of both proteins (Friedman et al., 1997). In adipocytes and in skeletal muscle, the stimulation of glucose transport by insulin is impaired. However, insulin signaling in adipocytes in the SHROB model has not yet been characterized.Akt (protein kinase B) is a 57-kDa Ser/Thr kinase that plays a key role in the insulin induced PI3K-Akt pathway (Hanada et al., 2004;Osaki et al., 2004). The binding of insulin to its receptors leads to the phosphorylation of PI3K, which then phosphorylates phosphatidylinositols at the 3-position. Then, Akt is recruited to the inner side of plasma membrane due to the interaction between its pleckstrin homology domain and the phosphatidylinositol-(3,4,5)-trisphosphate produced by PI3K. The Thr308 and Ser473 on Akt are then phosphorylated by 3-phosphoinositide-dependent protein kinase 1/2 and mammalian target of rapamycin (Hresko and Mueckler, 2005). Once activated, Akt regulates many cellular functions related to insulin action (Hanada et al., 2004). As a key element in insulin signaling, Akt could be an efficient indicator for cellular insulin response. Here, we measured the phosphorylation level of Akt in corresponding to insulin stimulation as an indicator of insulin sensitivity in isolated rat adipocytes. We hypothesized that the inherent defe...

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“…We have previously shown that while treatment of PC12 cells with NGF or moxonidine caused an increased phosphorylation of ERK, combination treatment with NGF and moxonidine resulted not in an expected increase in ERK phosphorylation, but rather a decrease. A decrease in ERK phosphorylation caused by the combination treatment of NGF and moxonidine was paralleled by an increase in MKP-2 induction [5]. Similarly, stimulation of angiotensin AT2 receptors in PC12 cells by angiotensin II, resulted in an enhanced phosphorylation of ERK within 10 min, compared to untreated cells.…”

Section: Effects Of Insulin Combined With S43126 On Phosphorylation Omentioning

confidence: 80%

“…There is an ongoing debate regarding the molecular identity of the I 1 R. Previous studies of IRAS-transfected CHO and PC12 cells have shown an elevation in radioligand binding to I 1 R sites, as well as an enhanced activation of PC-PLC and ERK phosphorylation by imidazoline agonists. These changes could be blocked by efaroxan, a selective I 1 R antagonist [5,6,18,25]. Similarly, PC12 cells transfected with cDNA encoding nischarin, increased I 1 R binding sites as shown by radioligand binding studies.…”

Section: Effects Of Nisch Sirna On Nischarin Protein Expression Erk mentioning

confidence: 84%

“…This was surprising since based on the concentration-response curves, the maximum ERK phosphorylation in response to insulin was seen at (10 -6 M) insulin and the maximum ERK response to S43126 was seen at 10 -9 M. Concentrations of agonists that increase ERK phosphorylation tend to also activate mitogen activated protein kinase phosphatases (MKP) [5]. We have previously shown that while treatment of PC12 cells with NGF or moxonidine caused an increased phosphorylation of ERK, combination treatment with NGF and moxonidine resulted not in an expected increase in ERK phosphorylation, but rather a decrease.…”

Section: Effects Of Insulin Combined With S43126 On Phosphorylation Omentioning

confidence: 99%

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Novel I1-imidazoline S43126 enhance insulin action in PC12 cells

Tesfai

Crane

Baziard-Mouysset

et al. 2011

Pharmacological Reports

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Abstract:The I 1 -imidazoline receptor is a novel target for drug development for hypertension and insulin resistance, major disorders associated with type 2 diabetes. In the present study, we examined the effects of a novel imidazoline agonist S43126, on phosphorylation of protein kinase B (PKB/Akt) and extracellular signal-regulated kinase (ERK1/2) in PC12 cells. We further examined the effects of S43126 on insulin stimulated PKB and ERK phosphorylation. PC12 cells were treated with varying doses of S43126 (10 -10 to 10 -6 M) or insulin (10 -10 to 10 -6 M) or combination treatment with insulin (10 -6 M) and varying doses of S43126 (10 -6 -10 -11 M) for 10 min. Western blot analysis of treated samples showed that S43126 increased both ERK1/2 and PKB phosphorylation by 5 fold. Combination treatment with insulin (10 -6 M) and varying doses of S43126 (10 -6 -10 -11 M) enhanced phosphorylation of PKB and ERK1/2 above the level of insulin alone, in a dose and time dependent manner. Treatment with siRNA against Nischarin (mouse homologue of I 1 -imidazoline receptor) reduced the phosphorylation of both ERK and PKB following combination treatments. These results indicate that S43126 has the potential to augment insulin action and should be further studied as a possible candidate drug for the treatment of insulin resistance states.

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The I1-imidazoline receptor in PC12 pheochromocytoma cells reverses NGF-induced ERK activation and induces MKP-2 phosphatase

Cited by 15 publications

References 30 publications

A New Pyrroline Compound Selective for I₁-Imidazoline Receptors Improves Metabolic Syndrome in Rats

A New Pyrroline Compound Selective for I₁-Imidazoline Receptors Improves Metabolic Syndrome in Rats

Marked Insulin Resistance in Obese Spontaneously Hypertensive Rat Adipocytes Is Ameliorated by in Vivo but Not in Vitro Treatment with Moxonidine

Novel I1-imidazoline S43126 enhance insulin action in PC12 cells

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The I1-imidazoline receptor in PC12 pheochromocytoma cells reverses NGF-induced ERK activation and induces MKP-2 phosphatase

Cited by 15 publications

References 30 publications

A New Pyrroline Compound Selective for I1-Imidazoline Receptors Improves Metabolic Syndrome in Rats

A New Pyrroline Compound Selective for I1-Imidazoline Receptors Improves Metabolic Syndrome in Rats

Marked Insulin Resistance in Obese Spontaneously Hypertensive Rat Adipocytes Is Ameliorated by in Vivo but Not in Vitro Treatment with Moxonidine

Novel I1-imidazoline S43126 enhance insulin action in PC12 cells

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A New Pyrroline Compound Selective for I₁-Imidazoline Receptors Improves Metabolic Syndrome in Rats

A New Pyrroline Compound Selective for I₁-Imidazoline Receptors Improves Metabolic Syndrome in Rats