PT-1 selectively activates AMPK-γ1 complexes in mouse skeletal muscle, but activates all three γ subunit complexes in cultured human cells by inhibiting the respiratory chain

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PT-1 selectively activates AMPK-γ1 complexes in mouse skeletal muscle, but activates all three γ subunit complexes in cultured human cells by inhibiting the respiratory chain. / Jensen, Thomas Elbenhardt; Ross, Fiona A; Kleinert, Maximilian; Sylow, Lykke; Knudsen, Jonas Roland; Gowans, Graeme J; Hardie, D Grahame; Richter, Erik A.

I: Biochemical Journal, Bind 467, Nr. 3, 2015, s. 461-472.

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Harvard

Jensen, TE, Ross, FA, Kleinert, M, Sylow, L, Knudsen, JR, Gowans, GJ, Hardie, DG & Richter, EA 2015, 'PT-1 selectively activates AMPK-γ1 complexes in mouse skeletal muscle, but activates all three γ subunit complexes in cultured human cells by inhibiting the respiratory chain', Biochemical Journal, bind 467, nr. 3, s. 461-472. https://doi.org/10.1042/BJ20141142

APA

Jensen, T. E., Ross, F. A., Kleinert, M., Sylow, L., Knudsen, J. R., Gowans, G. J., Hardie, D. G., & Richter, E. A. (2015). PT-1 selectively activates AMPK-γ1 complexes in mouse skeletal muscle, but activates all three γ subunit complexes in cultured human cells by inhibiting the respiratory chain. Biochemical Journal, 467(3), 461-472. https://doi.org/10.1042/BJ20141142

Vancouver

Jensen TE, Ross FA, Kleinert M, Sylow L, Knudsen JR, Gowans GJ o.a. PT-1 selectively activates AMPK-γ1 complexes in mouse skeletal muscle, but activates all three γ subunit complexes in cultured human cells by inhibiting the respiratory chain. Biochemical Journal. 2015;467(3):461-472. https://doi.org/10.1042/BJ20141142

Author

Jensen, Thomas Elbenhardt ; Ross, Fiona A ; Kleinert, Maximilian ; Sylow, Lykke ; Knudsen, Jonas Roland ; Gowans, Graeme J ; Hardie, D Grahame ; Richter, Erik A. / PT-1 selectively activates AMPK-γ1 complexes in mouse skeletal muscle, but activates all three γ subunit complexes in cultured human cells by inhibiting the respiratory chain. I: Biochemical Journal. 2015 ; Bind 467, Nr. 3. s. 461-472.

Bibtex

@article{858732f285604b6caea5c1f52c3d92de,
title = "PT-1 selectively activates AMPK-γ1 complexes in mouse skeletal muscle, but activates all three γ subunit complexes in cultured human cells by inhibiting the respiratory chain",
abstract = "AMP-activated protein kinase (AMPK) occurs as heterotrimeric complexes in which a catalytic subunit (α1/α2) is bound to one of two b subunits (β1/β2) and one of three γ subunits (γ1/γ2/γ3). The ability to selectively activate specific isoforms would be a useful research tool, and a promising strategy to combat diseases such as cancer and type 2 diabetes. We report that the AMPK activator PT-1 selectively increased the activity of γ1- but not γ3-containing complexes in incubated mouse muscle. PT-1 increased the AMPK-dependent phosphorylation of the autophagy-regulating kinase ULK1 on Ser555, but not proposed AMPK-γ3 substrates such as Ser231 on TBC1D1 or Ser212 on ACC2, nor did it stimulate glucose transport. Surprisingly, however, in HEK-293 cells expressing human γ1, γ2 or γ3, PT-1 activated all three complexes equally. We were unable to reproduce previous findings suggesting that PT-1 activates AMPK by direct binding between the kinase and auto-inhibitory domains of the α subunit. We show instead that PT-1 activates AMPK indirectly by inhibiting the respiratory chain and increasing cellular AMP:ATP and/or ADP:ATP ratios. Consistent with this mechanism, PT-1 failed to activate AMPK in HEK-293 cells expressing an AMP-insensitive R299G mutant of AMPK-γ1. We propose that the failure of PT-1 to activate γ3-containing complexes in muscle is not an intrinsic feature of such complexes, but is because PT-1 does not increase cellular AMP:ATP ratios in the specific subcellular compartment(s) in which γ3 complexes are located.",
author = "Jensen, {Thomas Elbenhardt} and Ross, {Fiona A} and Maximilian Kleinert and Lykke Sylow and Knudsen, {Jonas Roland} and Gowans, {Graeme J} and Hardie, {D Grahame} and Richter, {Erik A.}",
note = "CURIS 2015 NEXS 138",
year = "2015",
doi = "10.1042/BJ20141142",
language = "English",
volume = "467",
pages = "461--472",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "3",

}

RIS

TY - JOUR

T1 - PT-1 selectively activates AMPK-γ1 complexes in mouse skeletal muscle, but activates all three γ subunit complexes in cultured human cells by inhibiting the respiratory chain

AU - Jensen, Thomas Elbenhardt

AU - Ross, Fiona A

AU - Kleinert, Maximilian

AU - Sylow, Lykke

AU - Knudsen, Jonas Roland

AU - Gowans, Graeme J

AU - Hardie, D Grahame

AU - Richter, Erik A.

N1 - CURIS 2015 NEXS 138

PY - 2015

Y1 - 2015

N2 - AMP-activated protein kinase (AMPK) occurs as heterotrimeric complexes in which a catalytic subunit (α1/α2) is bound to one of two b subunits (β1/β2) and one of three γ subunits (γ1/γ2/γ3). The ability to selectively activate specific isoforms would be a useful research tool, and a promising strategy to combat diseases such as cancer and type 2 diabetes. We report that the AMPK activator PT-1 selectively increased the activity of γ1- but not γ3-containing complexes in incubated mouse muscle. PT-1 increased the AMPK-dependent phosphorylation of the autophagy-regulating kinase ULK1 on Ser555, but not proposed AMPK-γ3 substrates such as Ser231 on TBC1D1 or Ser212 on ACC2, nor did it stimulate glucose transport. Surprisingly, however, in HEK-293 cells expressing human γ1, γ2 or γ3, PT-1 activated all three complexes equally. We were unable to reproduce previous findings suggesting that PT-1 activates AMPK by direct binding between the kinase and auto-inhibitory domains of the α subunit. We show instead that PT-1 activates AMPK indirectly by inhibiting the respiratory chain and increasing cellular AMP:ATP and/or ADP:ATP ratios. Consistent with this mechanism, PT-1 failed to activate AMPK in HEK-293 cells expressing an AMP-insensitive R299G mutant of AMPK-γ1. We propose that the failure of PT-1 to activate γ3-containing complexes in muscle is not an intrinsic feature of such complexes, but is because PT-1 does not increase cellular AMP:ATP ratios in the specific subcellular compartment(s) in which γ3 complexes are located.

AB - AMP-activated protein kinase (AMPK) occurs as heterotrimeric complexes in which a catalytic subunit (α1/α2) is bound to one of two b subunits (β1/β2) and one of three γ subunits (γ1/γ2/γ3). The ability to selectively activate specific isoforms would be a useful research tool, and a promising strategy to combat diseases such as cancer and type 2 diabetes. We report that the AMPK activator PT-1 selectively increased the activity of γ1- but not γ3-containing complexes in incubated mouse muscle. PT-1 increased the AMPK-dependent phosphorylation of the autophagy-regulating kinase ULK1 on Ser555, but not proposed AMPK-γ3 substrates such as Ser231 on TBC1D1 or Ser212 on ACC2, nor did it stimulate glucose transport. Surprisingly, however, in HEK-293 cells expressing human γ1, γ2 or γ3, PT-1 activated all three complexes equally. We were unable to reproduce previous findings suggesting that PT-1 activates AMPK by direct binding between the kinase and auto-inhibitory domains of the α subunit. We show instead that PT-1 activates AMPK indirectly by inhibiting the respiratory chain and increasing cellular AMP:ATP and/or ADP:ATP ratios. Consistent with this mechanism, PT-1 failed to activate AMPK in HEK-293 cells expressing an AMP-insensitive R299G mutant of AMPK-γ1. We propose that the failure of PT-1 to activate γ3-containing complexes in muscle is not an intrinsic feature of such complexes, but is because PT-1 does not increase cellular AMP:ATP ratios in the specific subcellular compartment(s) in which γ3 complexes are located.

U2 - 10.1042/BJ20141142

DO - 10.1042/BJ20141142

M3 - Journal article

C2 - 25695398

VL - 467

SP - 461

EP - 472

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 3

ER -

ID: 131739473