See also Randriamboavonjy V, Fleming I. Energy and motion: AMPKa1 and its role in platelet activation. This issue, pp 970–2.
The Ca2+/calmodulin-dependent kinase kinase β-AMP-activated protein kinase-α1 pathway regulates phosphorylation of cytoskeletal targets in thrombin-stimulated human platelets
Article first published online: 10 JUN 2014
© 2014 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 12, Issue 6, pages 973–986, June 2014
How to Cite
The Ca2+/calmodulin-dependent kinase kinase β-AMP-activated protein kinase-α1 pathway regulates phosphorylation of cytoskeletal targets in thrombin-stimulated human platelets. J Thromb Haemost 2014; 12: 973–86., , , , , , , , , , , , , .
Manuscript handled by: S. Watson
Final decision: P. H. Reitsma, 11 March 2014
- Issue published online: 10 JUN 2014
- Article first published online: 10 JUN 2014
- Accepted manuscript online: 23 MAR 2014 11:25PM EST
- Manuscript Received: 23 SEP 2013
- Fonds National de la Recherche Scientifique
- Fonds Spéciaux de Recherche
- Université catholique de Louvain
- Salus Sanguinis Foundation
- AMP-activated protein kinase;
- platelet aggregation;
- signal transduction;
Platelet activation requires sweeping morphologic changes, supported by contraction and remodeling of the platelet actin cytoskeleton. In various other cell types, AMP-activated protein kinase (AMPK) controls the phosphorylation state of cytoskeletal targets.
To determine whether AMPK is activated during platelet aggregation and contributes to the control of cytoskeletal targets.
We found that AMPK-α1 was mainly activated by thrombin, and not by other platelet agonists, in purified human platelets. Thrombin activated AMPK-α1 ex vivo via a Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ)-dependent pathway. Pharmacologic inhibition of CaMKKβ blocked thrombin-induced platelet aggregation and counteracted thrombin-induced phosphorylation of several cytoskeletal proteins, namely, regulatory myosin light chains (MLCs), cofilin, and vasodilator-stimulated phosphoprotein (VASP), three key elements involved in actin cytoskeletal contraction and polymerization. Platelets isolated from mice lacking AMPK-α1 showed reduced aggregation in response to thrombin, and this was associated with defects in MLC, cofilin and VASP phosphorylation and actin polymerization. More importantly, we show, for the first time, that the AMPK pathway is activated in platelets of patients undergoing major cardiac surgery, in a heparin-sensitive manner.
AMPK-α1 is activated by thrombin in human platelets. It controls the phosphorylation of key cytoskeletal targets and actin cytoskeletal remodeling during platelet aggregation.