Abstract
Glucose-sensing (GS) behaviour in pancreatic β-cells is dependent on ATP-sensitive K+ channel (KATP) activity, which is controlled by the relative levels of the KATP ligands ATP and ADP, responsible for closing and opening KATP, respectively. However, the mechanism by which β-cells transfer energy status from mitochondria to KATP, and hence to altered electrical excitability and insulin secretion, is presently unclear. Recent work has demonstrated a critical role for AMP-activated protein kinase (AMPK) in GS behaviour of cells. Electrophysiological recordings, coupled with measurements of gene and protein expression were made from rat insulinoma cells to investigate whether AMPK activity regulates this energy transfer process. Using the whole-cell recording configuration with sufficient intracellular ATP to keep KATP closed, raised AMPK activity induced GS electrical behaviour. This effect was prevented by the AMPK inhibitor, compound C and required a phosphotransfer process. Indeed, high levels of intracellular phosphocreatine or the presence of the adenylate kinase (AK) inhibitor AP5A blocked this action of AMPK. Using conditions that maximised AMPK-induced KATP opening, there was a significant increase in AK1, AK2 and UCP2 mRNA expression. Thus we propose that KATP opening in response to lowered glucose concentration requires AMPK activity, perhaps in concert with increased AK and UCP2 to enable mitochondrial-derived ADP signals to be transferred to plasma membrane KATP by phosphotransfer cascades.
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Abraham MR, Selivanov VA, Hodgson DM, Pucar D, Zingman LV, Wieringa B, Dzeja PP, Alekseev AE, Terzic A (2002) Coupling of cell energetics with membrane metabolic sensing. J Biol Chem 277(27):24427–24434
Ainscow EK, Mirshamsi S, Tang T, Ashford MLJ, Rutter GA (2002) Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP-independent control of ATP-sensitive K+ channels. J Physiol 544(2):429–445. doi:10.1113/jphysiol.2002.022434
Ashcroft FM, Rorsman P (1990) ATP-sensitive K+ channels - a link between b-cell metabolism and insulin-secretion. Biochem Soc Trans 18(1):109–111
Ashcroft FM, Harrison DE, Ashcroft SJ (1984) Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature 312(5993):446–448
Ashcroft FM, Ashcroft SJH, Harrison DE (1988) Properties of single potassium channels modulated by glucose in rat pancreatic beta-cells. J Physiol 400:501–527
Beall C, Piipari K, Al-Qassab H, Smith MA, Parker N, Carling D, Viollet B, Withers DJ, Ashford MLJ (2010) Loss of AMP-activated protein kinase alpha 2 subunit in mouse beta-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia. Biochem J 429:323–333
Beall C, Hamilton DL, Gallagher J, Logie L, Wright KY, Soutar PM, Dadak S, Ashford F, Haythorne E, Du Q, Jovanovic A, McCrimmon RJ, Ashford ML (2012) Mouse hypothalamic GT1-7 cells demonstrate AMPK-dependent intrinsic glucose-sensing behaviour. Diabetologia 55(9):2432–2444
Buschard K, Blomqvist M, Mansson J-E, Fredman P, Juhl K, Gromada J (2006) C16: 0 sulfatide inhibits insulin secretion in rat beta-cells by reducing the sensitivity of K-ATP channels to ATP inhibition. Diabetes 55(10):2826–2834
Carrasco AJ, Dzeja PP, Alekseev AE, Pucar D, Zingman LV, Abraham MR, Hodgson D, Bienengraeber M, Puceat M, Janssen E, Wieringa B, Terzic A (2001) Adenylate kinase phosphotransfer communicates cellular energetic signals to ATP-sensitive potassium channels. Proc Natl Acad Sci U S A 98(13):7623–7628
Carrington CA, Rubery ED, Pearson EC, Hales CN (1986) 5 new insulin-producing cell-lines with differing secretory properties. J Endocrinol 109(2):193
Chang TJ, Chen WP, Yang C, Lu PH, Liang YC, Su MJ, Lee SC, Chuang LM (2009) Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats. Diabetologia 52(6):1112–1121
Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LG, Clements M, Al-Qassab H, Heffron H, Xu AW, Speakman JR, Barsh GS, Viollet B, Vaulont S, Ashford ML, Carling D, Withers DJ (2007) AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest 117(8):2325–2336
Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R, Zhao G, Marsh K, Kym P, Jung P, Camp HS, Frevert E (2006) Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 3(6):403–416
Crawford RM, Ranki HJ, Botting CH, Budas GR, Jovanovic A (2001) Creatine kinase is physically associated with the cardiac ATP-sensitive k(+) channel in vivo. FASEB J 15(13):102–104
Da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, Rutter GA (2003) Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulinexpression. Biochem J 371:761–774
Dufer M, Noack K, Krippeit-Drews P, Drews G (2010) Activation of the AMP-activated protein kinase enhances glucose-stimulated insulin secretion in mouse b-cells. Islets 2(3):156–163
Dzeja PP, Terzic A (1998) Phosphotransfer reactions in the regulation of ATP-sensitive K+ channels. FASEB J 12(7):523–529
Elvir-Mairena JR, Jovanovic A, Gomez LA, Alekseev AE, Terzic A (1996) Reversal of the ATP-liganded state of ATP-sensitive K+ channels by adenylate kinase activity. J Biol Chem 271(50):31903–31908
Ghosh A, Ronner P, Cheong E, Khalid P, Matschinsky FM (1991) The role of ATP and free ADP in metabolic coupling during fuel-stimulated insulin release from islet beta-cells in the isolated perfused rat pancreas. J Biol Chem 266(34):22887–22892
Goransson O, McBride A, Hawley SA, Ross FA, Shpiro N, Foretz M, Viollet B, Hardie DG, Sakamoto K (2007) Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J Biol Chem 282(45):32549–32560
Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13(4):251–262
Hong Y, Fink BD, Dillon JS, Sivitz WI (2001) Effects of adenoviral overexpression of uncoupling protein-2 and-3 on mitochondrial respiration in insulinoma cells. Endocrinology 142(1):249–256
Huss RJ, Glaser M (1983) Identification and purification of an adenylate kinase-associated protein that influences the thermostabilirt of adenylate kinase from a temperature-sensitive ADK mutant of Escherichia-Coli. J Biol Chem 258(21):3370–3376
Kakei M, Kelly RP, Ashcroft SJH, Ashcroft FM (1986) The Atp-sensitivity of K+ channels in rat pancreatic b-cells is modulated by Adp. FEBS Lett 208(1):63–66
Kennedy HJ, Pouli AE, Ainscow EK, Jouaville LS, Rizzuto R, Rutter GA (1999) Glucose generates sub-plasma membrane ATP microdomains in single islet beta-cells. Potential role for strategically located mitochondria. J Biol Chem 274(19):13281–13291
Kozlowski RZ, Hales CN, Ashford MLJ (1989) Dual effects of diazoxide on Atp-K+ currents recorded from an insulin-secreting cell-line. Br J Pharmacol 97(4):1039–1050
Krippeit-Drews P, Backer M, Dufer M, Drews G (2003) Phosphocreatine as a determinant of K-ATP channel activity in pancreatic beta-cells. Pflugers Arch Eur J Physiol 445(5):556–562
Larsson O, Deeney JT, Branstrom R, Berggren P-O, Corkey BE (1996) Activation of the ATP-sensitive K channel by long chain Acyl-CoA. J Biol Chem 271(18):10623–10626
Lederer WJ, Nichols CG (1989) Nucleotide modulation of the activity of rat heart ATP-sensitive K+ channels in isolated membrane patches. J Physiol 419(1):193–211
Lim A, Park S-H, Sohn J-W, Jeon J-H, Park J-H, Song D-K, Lee S-H, Ho W-K (2009) Glucose deprivation regulates KATP channel trafficking via AMP-activated protein kinase in pancreatic {beta}-cells. Diabetes 58(12):2813–2819
Mirshamsi S, Laidlaw HA, Ning K, Anderson E, Burgess LA, Gray A, Sutherland C, Ashford MLJ (2004). Leptin and insulin stimulation of signalling pathways in arcuate nucleus neurones: PI3K dependent actin reorganization and K-ATP channel activation. Bmc Neurosci 5
Neumann D, Schlattner U, Wallimann T (2003) A molecular approach to the concerted action of kinases involved in energy homoeostasis. Biochem Soc Trans 31:169–174
Nichols CG, Lederer WJ (1990) The regulation Of ATP-sensitive K+ channel aactivity in intact and permeabilized rat ventricular myocytes. J Physiol 423:91–110
Olson LK, Schroeder W, Robertson RP, Goldberg ND, Walseth TF (1996) Suppression of adenylate kinase catalyzed phosphotransfer precedes and is associated with glucose-induced insulin secretion in intact HIT-T15 cells. J Biol Chem 271(28):16544–16552
Ponticos M, Lu Q, Morgan JE, Hardie DG, Partridge TA, Carling D (1998) Dual regulation of the AMP-activated protein kinase provides a novel mechanism for the control of creatine kinase in skeletal muscle. EMBO J 17(6):1688–1699
Rooney K, Bryson J, Phuyal J, Denyer G, Caterson I, Thompson C (2002) Creatine supplementation alters insulin secretion and glucose homeostasis in vivo. Metab Clin Exp 51(4):518–522
Schulze DU, Duefer M, Wieringa B, Krippeit-Drews P, Drews G (2007) An adenylate kinase is involved in K(ATP) channel regulation of mouse pancreatic beta cells. Diabetologia 50(10):2126–2134
Shyng S-L, Nichols CG (1998) Membrane phospholipid control of nucleotide sensitivity of KATP channels. Science 282(5391):1138–1141
Sim ATR, Hardie DG (1988) The low activity of acetyl-CoA carboxylase in basal and glucagon-stimulated hepatocytes is due to phosphorylation by the AMP-activated protein kinase and not cyclic AMP-dependent protein kinase. FEBS Lett 233(2):294–298
Stanojevic V, Habener JF, Holz GG, Leech CA (2008) Cytosolic adenylate kinases regulate K-ATP channel activity in human beta-cells. Biochem Biophys Res Commun 368(3):614–619
Sun G, Tarasov AI, McGinty J, McDonald A, da Silva Xavier G, Gorman T, Marley A, French PM, Parker H, Gribble F, Reimann F, Prendiville O, Carzaniga R, Viollet B, Leclerc I, Rutter GA (2010) Ablation of AMP-activated protein kinase alpha 1 and alpha 2 from mouse pancreatic beta cells and RIP2.Cre neurons suppresses insulin release in vivo. Diabetologia 53(5):924–936
Tarasov AI, Girard CAJ, Ashcroft FM (2006) ATP sensitivity of the ATP-Sensitive K(+) channel in intact and permeabilized pancreatic beta-cells. Diabetes 55(9):2446–2454
Tsuboi T, da Silva Xavier G, Leclerc I, Rutter GA (2003) 5′-AMP-activated protein kinase controls insulin-containing secretory vesicle dynamics. J Biol Chem 278(52):52042–52051
Van Rompay AR, Johansson M, Karlsson A (2000) Phosphorylation of nucleosides and nucleoside analogs by mammalian nucleoside monophosphate kinases. Pharmacol Ther 87(2–3):189–198
Vanderlijn P, Barrio JR, Leonard NJ (1979) Inhibition of adenylate kinase by P1-(Lin-benzo-5′-adenosyl)-P4-(5′-adenolsyl) tetraphosphate and P1-(lin-benzi-5′-adenosyl)-P5-(5′-adenosyl) pentaphosphate. Biochemistry 18(25):5557–5561
Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM (1992) Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demans - the phosphocreatine circuit for cellular-energy homeostasis. Biochem J 281:21–40
Wang CZ, Wang Y, Di A, Magnuson MA, Ye HG, Roe MW, Nelson DJ, Bell GI, Philipson LH (2005) 5-Amino-imidazole carboxamide riboside acutely potentiates glucose-stimulated insulin secretion from mouse pancreatic islets by K-ATP channel-dependent and -independent pathways. Biochem Biophys Res Commun 330(4):1073–1079
Wang Y, Nishi M, Doi A, Shono T, Furukawa Y, Shimada T, Furuta H, Sasaki H, Nanjo K (2010) Ghrelin inhibits insulin secretion through the AMPK–UCP2 pathway in β cells. FEBS Lett 584(8):1503–1508
Weiss JN, Lamp ST (1987) Glycolysis preferentially inhibits ATP-sensitive K+ channels in isolated guina-pig cardiac myocytes. Science 238(4823):67–69
Yoshida H, Bao L, Kefaloyianni E, Taskin E, Okorie U, Hong M, Dhar-Chowdhury P, Kaneko M, Coetzee WA (2012) AMP-activated protein kinase connects cellular energy metabolism to KATP channel function. J Mol Cell Cardiol 52(2):410–418
Zhang C-Y, Baffy GR, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig AJ, Boss O, Kim Y-B, Zheng XX, Wheeler MB, Shulman GI, Chan CB, Lowell BB (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, b-cell dysfunction, and type 2 diabetes. Cell 105(6):745–755
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Investig 108(8):1167–1174
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Beall, C., Watterson, K.R., McCrimmon, R.J. et al. AMPK modulates glucose-sensing in insulin-secreting cells by altered phosphotransfer to KATP channels. J Bioenerg Biomembr 45, 229–241 (2013). https://doi.org/10.1007/s10863-013-9509-9
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DOI: https://doi.org/10.1007/s10863-013-9509-9