This Review is part of a thematic series on AMP Kinase, which includes the following articles:
AMP-Activated Protein Kinase in Metabolic Control and Insulin Signaling
Cardiac AMP-Activated Protein Kinase in Health and Disease
Bruce Kemp, Guest Editor
AMP-Activated Protein Kinase in Metabolic Control and
Mhairi C. Towler, D. Grahame Hardie
Abstract—The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all
eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere
with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction).
Activation in response to increases in AMP involves phosphorylation by an upstream kinase, the tumor suppressor LKB1. In
certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca2?-dependent and
AMP-independent process involving phosphorylation by an alternate upstream kinase, CaMKK?. Once activated, AMPK
switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and
cell growth and proliferation. The AMPK complex contains 3 subunits, with the ? subunit being catalytic, the ? subunit
containing a glycogen-sensing domain, and the ? subunits containing 2 regulatory sites that bind the activating and inhibitory
nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and
cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in
maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of
exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for
obesity, type 2 diabetes, and the metabolic syndrome. (Circ Res. 2007;100:328-341.)
Key Words: calcium signaling ? diabetes ? insulin ? metabolism ? signaling pathways
eukaryotic species in which genome sequences have been
completed, including vertebrates and invertebrates, plants, fungi,
and protozoa.1Genetic studies show that in the yeast Saccharo-
myces cerevisiae, the genes encoding these subunits are required
for the response to glucose starvation.2,3In a primitive green
plant, the moss Physcomitrella patens, genes encoding the
catalytic subunits are required for growth in alternate light/dark
cycles, as opposed to continuous light.4Darkness represents a
period of starvation for a green plant because it is unable to
produce carbohydrate by photosynthesis. The AMPK system
therefore appears to have initially evolved to execute responses
to carbon starvation. Because of the sophisticated endocrine
enes encoding the ?, ?, and ? subunits of the AMP-acti-
vated protein kinase (AMPK) are highly conserved in all
the effects of insulin), starvation for glucose is not a normal
physiological event for mammalian cells in vivo. Nevertheless,
it is involved in the response to a variety of metabolic stresses
that disturb cellular energy homeostasis. More recently, it has
been realized that hormones and other extracellular signals have
known to be involved in regulating energy homeostasis at the
whole body, as well as the cellular, levels.
Regulation of the AMPK Complex by 5?-AMP
With hindsight, the first reports describing the AMPK system
were 2 independent articles published in 1973 involving
Original received October 26, 2006; revision received November 30, 2006; accepted December 12, 2006.
From the Division of Molecular Physiology, College of Life Sciences, University of Dundee, Scotland, UK.
Correspondence to Prof D. G. Hardie, Division of Molecular Physiology, College of Life Sciences, University of Dundee, Sir James Black Centre, Dow
St, Dundee, DD1 5EH, Scotland, UK. E-mail email@example.com
© 2007 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.orgDOI: 10.1161/01.RES.0000256090.42690.05
poorly defined protein fractions that, in the presence of ATP,
inactivated 2 key metabolic enzymes involved in lipid syn-
thesis, ie, acetyl-CoA carboxylase (ACC) (involved in fatty
acid synthesis)5and 3-hydroxy-3-methylglutaryl-CoA
(HMG-CoA) reductase (involved in isoprenoid/cholesterol
synthesis).6The protein fractions were correctly surmised to
contain protein kinases, and subsequent studies revealed that
both the ACC kinase and the HMG-CoA reductase kinase
were stimulated by 5?-AMP.7,8However, it was not realized
that both functions were performed by the same protein
kinase until our laboratory provided evidence in favor of that
hypothesis in 19879; we renamed the activity AMP-activated
protein kinase the following year.10
As well as allosterically activating the enzyme by up to
5-fold,9AMP also promotes its phosphorylation11at a spe-
cific threonine residue on the ? subunit (Thr17212) by an
upstream kinase that has recently been identified as a com-
plex between the tumor suppressor protein LKB1 and 2
accessory subunits, termed STRAD and MO25.13,14Phos-
phorylation of Thr172 produces at least 100-fold activation,15
so that it is quantitatively much more important than the
allosteric activation. The LKB1 complex is not itself acti-
vated by AMP, and the effect of the nucleotide is to make
AMPK a better substrate for LKB1,13while at the same time
making it a worse substrate for protein phosphatases that
dephosphorylate Thr172.16The 3 effects of AMP make the
system very sensitive to small increases in AMP.17All 3
effects are also antagonized by high concentrations of ATP.
Because all eukaryotic cells express very active adenylate
kinases, which maintains their reaction (2ADP7
AMP?ATP) close to equilibrium at all times, the cellular
AMP:ATP ratio varies approximately as the square of the
ADP:ATP ratio,18making it a very sensitive indicator of
cellular energy status.
In cells lacking LKB1, such as HeLa cells (tumor cells in
which LKB1 is not expressed), there is still some basal
phosphorylation of Thr172 and AMPK activity,13and both
can be dramatically increased by addition of a Ca2?iono-
phore. Three groups have now identified the upstream kinase
responsible for phosphorylation of Thr172 under these cir-
cumstances as Ca2?/calmodulin-dependent protein kinase ki-
nase (CaMKK), especially the CaMKK? (CaMKK2) iso-
form.19–21CaMKKs were originally identified as protein
kinases that acted upstream of calmodulin-dependent protein
kinases I and IV.22Our laboratory showed that a purified
CaMKK could phosphorylate and activate AMPK in cell-free
assays as long ago as 1995,11although at that time, we did not
consider that this was likely to have any physiological
relevance. CaMKK? is expressed primarily in the brain but is
also expressed in testis, thymus, and T cells.23Our laboratory
has shown that when Ca2?enters neurones in rat brain slices
following K?-induced depolarization, there is a marked phos-
phorylation of Thr172 and activation of AMPK that is
catalyzed by a CaMKK.
Given the limited tissue distribution of the CaMKKs
compared with LKB1, the Ca2?-mediated pathway may be
restricted to certain cell types such as neurones, although
additional examples are discussed below. However, it is
interesting to speculate about the function of the
CaMKK3AMPK pathway in those cell types in which it
occurs. Any treatment that causes an increase in cytoplasmic
Ca2?will create a subsequent demand for ATP, if only
because the Ca2?is immediately pumped out of the cytoplasm
using ATP-driven pumps in the plasma membrane and
endoplasmic reticulum. Activation of AMPK under these
circumstances may represent a mechanism to anticipate the
demand for ATP created by Ca2?entry.
Subunit Structure of the AMPK Complex
AMPK is a heterotrimer comprising ?, ?, and ? subunits.
There are 2 or 3 genes encoding each subunit (Figure 1 and
Table 1), giving rise to 12 possible heterotrimeric combina-
tions, with splice variants further increasing the potential
diversity. The 2 isoforms of the ? subunit, ?124and ?2,25
contain the kinase domain in their N-terminal half, with the
C-terminal regions being required to form a complex with the
? and ? subunits.26They appear to have rather similar
substrate specificities,27but the ?2isoform is enriched in the
nucleus of several cell types, including pancreatic ? cells,28
neurones,29and skeletal muscle,30whereas ?1is predomi-
nantly cytoplasmic. The ?1isoform is associated with the
plasma membrane in carotid body type 1 cells31and airway
epithelial cells,32in the latter case particularly with the apical
The ? subunits from different eukaryotic species contain 2
conserved regions, located in the central and C-terminal
regions (Figure 1).33It is now clear that the C-terminal
domain is all that is required to form a functional ???
Figure 1. Domain structure of AMPK subunit isoforms and
splice variants. Regions shown in the same color are related,
and their functions, where known, are indicated.
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Towler and Hardie AMPK in Metabolic Control and Insulin Signaling