AMP-Activated Protein Kinase Is Activated by the Stimulations of Gq-Coupled Receptors

Kishi, Kazuhiro; Yuasa, Tomoyuki; Minami, Asako; Yamada, Mizuki; Hagi, Akifumi; Hayashi, Hideki; Kemp, Bruce E.; Witters, Lee A.; Ebina, Yasuhiko

doi:10.1006/bbrc.2000.3417

Cited by 66 publications

(47 citation statements)

References 54 publications

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“…A previous report showed that plasma membrane receptors coupled to the phosphoinositide signal transduction system through the G-proteins Gq and G11 activate AMPK [60]. More specifically, stimulation of Gq/11-coupled muscarinic receptors by carbachol was shown to activate AMPK in rat parotid acinar cells [40].…”

Section: Discussionmentioning

confidence: 95%

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

King

Lee

Jope

2006

Biochemical Pharmacology

122

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AMP-activated protein kinase (AMPK) is a key cellular sensor of reduced energy supply that is activated by increases in the cellular ratio of AMP/ATP. Phenformin and 5-aminoimida-zole-4-carboxamide riboside (AICAR) are two drugs widely used to activate AMPK experimentally. In both differentiated hippocampal neurons and neuroblastoma SH-SY5Y cells we found that these two agents not only activated AMPK, but conversely greatly reduced the activating Ser/Thr phosphorylation of Akt. This blockade of Akt activity consequently lowered the inhibitory serinephosphorylation of its substrates, glycogen synthase kinase-3a/b (GSK3a/b). An inhibitor of AMPK (Compound C) did not block dephosphorylation of Akt and GSK3. Thus, both drugs widely used to activate AMPK also caused dephosphorylation of Akt and of GSK3. The mechanism for Akt dephosphorylation caused by phenformin, but not AICAR, was due to inhibition of growth factorinduced signaling that leads to Akt phosphorylation. Stimulation of muscarinic receptors with carbachol in SH-SY5Y cells also activated AMPK and transiently caused dephosphorylation of Akt. These findings show that Akt dephosphorylation often occurs concomitantly with AMPK activation when cells are treated with phenformin or AICAR, indicating that these drugs do not only affect AMPK but also cause a coordinated inverse regulation of AMPK and Akt.

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Section: Discussionmentioning

confidence: 95%

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

King

Lee

Jope

2006

Biochemical Pharmacology

122

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“…we and other groups previously reported that stimulation of gαqPcrs activated amPK using an in vitro kinase assay with the anti-amPK antibody and a synthetic peptide substrate for amPK [36][37][38]. in this report, we investigated activation of amPK by immunoblot using anti phospho-amPK antibodies.…”

Section: Rt-pcrmentioning

confidence: 89%

“…Furthermore, we and other groups reported that activation of gαqPcr induced amPK activity [36][37][38]. Thus, we proposed that glucose transported by insulin or gαq activation has a distinct destination in cells; glucose transported into cells after gαq activation is immediately metabolized and consumed as an availability of cellular energy as well as aTP which the gαq-induced amPK activation supplied through activation of aTP-generating pathways and the decrease of aTP expenditure by suppressing macromolecule synthesis [39].…”

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confidence: 94%

The Rab GTPase-Activating Protein AS160 as a Common Regulator of Insulin- and G.ALPHA.q-Mediated Intracellular GLUT4 Vesicle Distribution

et al. 2009

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Abstract. Akt substrate of 160kDa (AS160) is a Rab GTPase activating protein (GAP) and was recently identified as a component of the insulin signaling pathway of glucose transporter type 4 (gLuT4) translocation. we and others, previously reported that the activation of gαq protein-coupled receptors (gαqPcrs) also stimulated gLuT4 translocation and glucose uptake in several cell lines. here, we report that the activation of gαqPcrs also promoted phosphorylation of as160 by the 5'-AMP activated protein kinase (AMPK). The suppression of AS160 phosphorylation by the siRNA mediated AMPKα1 subunit knockdown promoted gLuT4 vesicle retention in intracellular compartments. This suppression did not affect the ratio of non-induced cell surface GLUT4 to Gαq-induced it. Rat 3Y1 cells lacking AS160 did not show insulin-induced GLUT4 translocation. The cells stably expressing gLuT4 revealed gLuT4 vesicles that were mainly localized in the perinuclear region and less frequently on the cell surface. after expression of exogenous as160, gLuT4 on the cell surface decreased and GLUT4 vesicles were redistributed throughout the cytoplasm. Although PMA-induced or sodium fluoride-induced GLUT4 translocation was significantly increased in these cells, insulin did not affect GLUT4 translocation. These results suggest that AS160 is a common regulator of insulin-and GαqPCR activation-mediated GLUT4 distribution in the cells.Key words: AS160, Gαq protein-coupled receptor, AMPK, GLUT4(Endocrine Journal 56: [345][346][347][348][349][350][351][352][353][354][355][356][357][358][359] 2009) Glucose metabolism is crucial throughout the body to facilitate glucose transport into the muscle and adipocytes by insulin [1]. insulin binds to its own receptors on these cell surfaces, thereby activating their intrinsic tyrosine kinase, followed by the activation of phosphatidylinositol-3 kinase (Pi-3K) and akt. glucose transport is consequently stimulated, mainly due to translocation of glucose transporter type 4 (gLuT4) from an intracellular membrane compartment to the cell surface [2]. in addition, we and others reported that platelet-derived growth factor (PDgF) and epidermal growth factor, which can activate Pi

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“…Materials-Phentolamine, propranolol, and isoproterenol were purchased from Sigma, AKT inhibitor (10-DEBC) was purchased from Tocris USA, and PKA inhibitor (PKA-I, [14][15][16][17][18][19][20][21][22] was purchased from Calbiochem.…”

Section: Methodsmentioning

confidence: 99%

“…The effects of leptin through the hypothalamus on muscle AMPK involve ␣-adrenergic receptors in muscle (8). The ␣-adrenergic agonist, phenylephrine, activates AMPK in isolated soleus muscle, C2C12 myocytes, and CHO cells (8,14,15), whereas the ␤-adrenergic agonist, isoproterenol, stimulates AMPK in isolated adipocytes (16). Norepinephrine and epinephrine, both dual ␣ and ␤ agonists, activate AMPK in brown adipocytes in vitro (17) and white adipocytes ex vivo (18), and in the latter, activation of AMPK was necessary for maximal activation of lipolysis (18).…”

mentioning

confidence: 99%

Adrenergic Regulation of AMP-activated Protein Kinase in Brown Adipose Tissue in Vivo

Pulinilkunnil

Kong

et al. 2011

Journal of Biological Chemistry

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AMP-activated protein kinase (AMPK), an evolutionarily conserved serine-threonine kinase that senses cellular energy status, is activated by stress and neurohumoral stimuli. We investigated the mechanisms by which adrenergic signaling alters AMPK activation in vivo. Brown adipose tissue (BAT) is highly enriched in sympathetic innervation, which is critical for regulation of energy homeostasis. We performed unilateral denervation of BAT in wild type (WT) mice to abolish neural input. Six days post-denervation, UCP-1 protein levels and AMPK ␣2 protein and activity were reduced by 45%. In ␤ 1,2,3 -adrenergic receptor knock-out mice, unilateral denervation led to a 25-45% decrease in AMPK activity, protein expression, and Thr 172 phosphorylation. In contrast, acute ␣-or ␤-adrenergic blockade in WT mice resulted in increased AMPK ␣ Thr 172 phosphorylation and AMPK ␣1 and ␣2 activity in BAT. But short term blockade of ␣-adrenergic signaling in ␤ 1,2,3 -adrenergic receptor knock-out mice resulted in decreased AMPK activity in BAT, which strongly correlated with enhanced phosphorylation of AMPK on Ser 485/491 , a site associated with inhibition of AMPK activity. Both PKA and AKT inhibitors attenuated AMPK Ser 485/491 phosphorylation resulting from ␣-adrenergic blockade and prevented decreases in AMPK activity. In vitro mechanistic studies in BAT explants showed that the effects of ␣-adrenergic blockade appeared to be secondary to inhibition of oxygen consumption. In conclusion, adrenergic pathways regulate AMPK activity in vivo acutely via alterations in Thr 172 phosphorylation and chronically through changes in the ␣ catalytic subunit protein levels. Furthermore, AMPK ␣ Ser 485/491 phosphorylation may be a novel mechanism to inhibit AMPK activity in vivo and alter its biological effects. AMP-activated protein kinase (AMPK),4 an evolutionarily conserved serine threonine kinase, is a fuel-sensing enzyme complex activated by cellular stresses that increase AMP or deplete ATP including hypoxia, ischemia, glucose deprivation, uncouplers of oxidative phosphorylation, exercise, and muscle contraction (1, 2). Once activated, AMPK phosphorylates multiple downstream substrates that function to preserve the AMP: ATP ratio through inhibition of ATP-catabolizing pathways and promotion of ATP-generating pathways. Mechanisms involved in AMPK activation include 1) binding of AMP to an allosteric site on the ␥ subunit, which renders the holoenzyme resistant to inactivating serine phosphatases and may also have direct allosteric effects on kinase activity (1, 2) and 2) phosphorylation by upstream AMPK kinases of the ␣ (catalytic) subunits on Thr 172 , which is essential for kinase activity. Recent studies employing INS-1 cells (3), hepatitis C virus harboring replicon cells (4), and isolated heart preparations (5) have demonstrated another potential regulatory mechanism; that is, AMPK may also undergo inhibitory phosphorylation on serine 485 and 491 residues of the ␣1 and ␣2 catalytic subunits, respectively. Some data suggest that upstr...

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AMP-Activated Protein Kinase Is Activated by the Stimulations of Gq-Coupled Receptors

Cited by 66 publications

References 54 publications

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

The Rab GTPase-Activating Protein AS160 as a Common Regulator of Insulin- and G.ALPHA.q-Mediated Intracellular GLUT4 Vesicle Distribution

Adrenergic Regulation of AMP-activated Protein Kinase in Brown Adipose Tissue in Vivo

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