ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2006) 12 S24

AMPK cascade – new players upstream and downstream

IP Salt

University of Glasgow, Glasgow, United Kingdom.

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that has been proposed to act as an important regulator of both cellular and organismal energy homeostasis. Increases in the cellular AMP: ATP ratio promotes phosphorylation and activation of AMPK by the upstream kinase LKB1. AMPK subsequently phosphorylates target proteins that inhibit ATP-consuming anabolic pathways and stimulates ATP-producing catabolic pathways. AMPK is therefore activated by conditions that deplete ATP, such as hypoxia, hypoglycaemia and ischaemia. Furthermore, AMPK has been demonstrated to be activated in response to exercise in skeletal muscle and mediates some of the physiological effects of the antidiabetic drug metformin and the adipokines, adiponectin and leptin. Recent studies have indicated that AMPK can also be phosphorylated and activated by CaMKKβ, thereby responding to changes in Ca2+ independently of changes in the AMP/ATP ratio.

AMPK is the focus of considerable interest as a therapeutic target for the treatment of type 2 diabetes and the metabolic syndrome, which are both associated with endothelial dysfunction and cardiovascular disease, yet the role of AMPK in the endothelium is poorly characterised. Ongoing studies within our group are aimed at understanding the role of AMPK in the endothelium. We, and others have demonstrated that AMPK phosphorylates and activates endothelial nitric oxide (NO) synthase (eNOS) in cultured endothelial cells. Recent studies in our laboratory have indicated that AMPK mediates the stimulation of NO synthesis in response to several agonists. In addition, we have studied the functional effects of AMPK activation in the endothelium and have demonstrated that AMPK activation reduces leukocyte adhesion to cultured endothelial cells. Such data indicate an anti-atherogenic role for the AMPK cascade.

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