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Molecular and Cellular Biology, August 2006, p. 5933-5945, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.00383-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Thrombin Activates AMP-Activated Protein Kinase in Endothelial Cells via a Pathway Involving Ca2+/Calmodulin-Dependent Protein Kinase Kinase ß

Nadine Stahmann,1 Angela Woods,2 David Carling,2 and Regine Heller1*

Institute of Molecular Cell Biology, Friedrich Schiller University of Jena, Jena, Germany,1 Cellular Stress Group, MRC Clinical Science Centre, Imperial College, Hammersmith Hospital, London, United Kingdom2

Received 3 March 2006/ Returned for modification 7 April 2006/ Accepted 26 May 2006

AMP-activated protein kinase (AMPK) is a sensor of cellular energy state in response to metabolic stress and other regulatory signals. AMPK is controlled by upstream kinases which have recently been identified as LKB1 or Ca2+/calmodulin-dependent protein kinase kinase ß (CaMKKß). Our study of human endothelial cells shows that AMPK is activated by thrombin through a Ca2+-dependent mechanism involving the thrombin receptor protease-activated receptor 1 and Gq-protein-mediated phospholipase C activation. Inhibition of CaMKK with STO-609 or downregulation of CaMKKß using RNA interference decreased thrombin-induced AMPK activation significantly, indicating that CaMKKß was the responsible AMPK kinase. In contrast, downregulation of LKB1 did not affect thrombin-induced AMPK activation but abolished phosphorylation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleoside. Thrombin stimulation led to phosphorylation of acetyl coenzyme A carboxylase (ACC) and endothelial nitric oxide synthase (eNOS), two downstream targets of AMPK. Inhibition or downregulation of CaMKKß or AMPK abolished phosphorylation of ACC in response to thrombin but had no effect on eNOS phosphorylation, indicating that thrombin-stimulated phosphorylation of eNOS is not mediated by AMPK. Our results underline the role of Ca2+ as a regulator of AMPK activation in response to a physiologic stimulation. We also demonstrate that endothelial cells possess two pathways to activate AMPK, one Ca2+/CaMKKß dependent and one AMP/LKB1 dependent.

* Corresponding author. Mailing address: Institute of Molecular Cell Biology, Friedrich Schiller University of Jena, Nonnenplan 2, 07743 Jena, Germany. Phone: 49-3641-938 750. Fax: 49-3641-938 752. E-mail: regine.heller{at}mti.uni-jena.de.

Molecular and Cellular Biology, August 2006, p. 5933-5945, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.00383-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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