Systems Level Regulation of Cardiac Energy Fluxes Via Metabolic Cycles: Role of Creatine, Phosphotransfer Pathways, and AMPK Signaling - Systems Biology of Metabolic and Signaling Networks - page 280

11.5.2 Network Elements: AMPK Isoforms and Their
Distribution in Cells and Tissues

AMPK is an evolutionary conserved and ubiquitously expressed serine/threonine
kinase that presents complex structural and functional features. Structurally, it
occurs in vertebrates as an obligatory heterotrimeric complex composed of one
catalytic subunit ( α ) and two regulatory subunits ( β and γ ). As a first layer of

complexity, all subunits exist in form of different isoforms ( α 1, α 2, β 1, β 2, γ 1, γ 2,

and 3), generating multiple heterotrimeric

complexes. The precise physiological significance of these isoforms is not yet
entirely clear. However, there is some evidence that they determine intracellular
distribution, protein recognition, or tissue-specific functions of AMPK, all of which
could provide selectivity for specific subsets of substrates within the ever increasing
list of AMPK substrates (Hardie et al. 2012a , b ; Carling et al. 2012 ).

γ 3) and splice variants (of γ 2 and γ

11.5.2.1 Subcellular Localization

The subcellular distribution and recruitment of AMPK to specific sites are likely an
important factor for its signaling function, but so far only few details are known, in
particular in heart. AMPK is generally observed as a soluble complex with diffuse
cytosolic localization, but at least

2-containing complexes in their activated form
can translocate into the nucleus to phosphorylate important substrates (e.g., tran-
scription factors, histones, histone deacetylases) as seen, e.g., after exercise in
skeletal muscle (McGee et al. 2003 , 2008 ; Suzuki et al. 2007 ; McGee and
Hargreaves 2008 ). Minor but important portions of AMPK may associate with
cellular structures like specific membranes, where processes are regulated by
AMPK (e.g., ion channel activity, cell polarity, or cell junction formation) (Forcet
and Billaud 2007 ; Andersen and Rasmussen 2012 ; Nakano and Takashima 2012 ).
Myristoylation of the AMPK

α

-subunit can localize the kinase complex to
membranes and increases its activability, possibly favoring activation of
membrane-bound complexes (Suzuki et al. 2007 ; Oakhill et al. 2010 ).
AMPK may also be recruited into specific complexes via interaction with its
upstream kinases, downstream substrates, or more general scaffolding proteins.
However, the AMPK interactome is only partially known so far from some targeted
and non-biased interaction studies conducted by us and others (e.g., Ewing
et al. 2007 ; Moreno et al. 2009 ; Behrends et al. 2010 ; Klaus et al. 2012 ), and
more research is needed on this issue, in particular in the heart. AMPK interaction
with LKB1, its major upstream kinase in the heart, could localize AMPK to places
of LKB1 localization, including the mitochondrial surface or E-cadherin in
adherens junctions (Sebbagh et al. 2009 ). Scaffolding proteins can provide speci-
ficity in cell signaling by isolating activated kinases from bulk signaling and
directing the information flow into specific pathways. In heart, for example,
AMPK competes with p38 MAPK for binding to the scaffolding protein

β