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 281

TAK-1-binding protein-1, thus blunting p38 activation during ischemia
(Li et al. 2005 ). Mitochondrial VDAC may represent yet another anchor protein
recruiting AMPK to this organelle (Strogolova et al. 2012 ). There is also some
evidence that AMPK subunit isoforms determine specific protein interactions. The
β

-subunit may in some cases confer substrate specificity, as seen with the yeast and
plant orthologues (Vincent and Carlson 1999 ; Polge et al. 2008 ), but also putative
mammalian AMPK interactors (IntAct database, (Kerrien et al. 2012 )). We recently
found the 2-isoform interacting with Mu- and Pi-type glutathione transferases

(GSTs) to favor glutathionylation of the α -subunit (Klaus et al. 2013 ). However,
in case of fumarate hydratase (FH), we identified a specific interaction with
α

β

2-containing AMPK complexes (Klaus et al. 2012 ).

11.5.2.2 Expression Patterns

AMPK isoforms also show some differences in their tissue- and developmental-
specific expression patterns, also in heart, although the physiological significance is
still uncertain. While the

1 complex is probably the most abundant in most
cell types, differences seem to occur in the amount of additional isoforms like

α 1 β 1 γ

α 2-

and γ 3 in skeletal muscle or β 2 and a specific intermediate length γ 2 splice variant

( 2-3B) in the heart (Stapleton et al. 1996 ; Thornton et al. 1998 ; Li et al. 2006 ;

Pinter et al. 2012 ). There are also pathological and developmental changes in
cardiac AMPK expression. The

γ

2 isoforms are all upregulated by
pressure overload or heart failure in rodents, although in patients rather the content
of

α 2, β 2, and γ

2 (an intermediate form) increases with different forms of cardio-
myopathy (Tian et al. 2001 ; Kim et al. 2012 ). During embryonic development in
rodents,

α 1, β 1, and γ

γ 1 increases while high levels of γ 3 disappear, and the embryonically

predominant full-length 2b in

other tissues (Pinter et al. 2012 ). These developmental and tissue particularities
may also explain why

γ 2 form is replaced by γ 2-3B in heart, but by short γ

2 gene mutations in the CBS domains cause heriditary
hypertrophic cardiomyopathy (see below) but no other pathological symptoms.
Full-length γ 2 and γ 2-3B share an N-terminal domain with unknown function
that could localize the AMPK complex to specific compartments or signaling
pathways (Pinter et al. 2012 ). Total AMPK activity increases after birth,
contributing to the switch to predominant use of fatty acids (Makinde
et al. 1997 ). AMPK levels may also be determined by ubiquitin-dependent
mechanisms (Qi et al. 2008 ; Moreno et al. 2010 ), but its role in the heart is not
known.

γ

11.5.3 Network Elements: Molecular Structure of AMPK

Given the interest in AMPK as a putative drug target in metabolic diseases, recent
years have seen intense efforts to elucidate the molecular structure of AMPK.