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examine when during metazoan evolution AMP has been established as a second
messenger for energy stress and activation of AMPK. Creatine kinase and other
closely homologous phosphagen kinases have emerged quite early at the dawn of
the radiation of metazoans (Ellington 2001 ; Ellington and Suzuki 2007 ). Recently,
besides identifying arginine kinase in unicellular organisms, a novel taurocyamine
phosphagen kinase has been identified even in a unicellular protist
(Uda
et al. 2013 ).
In addition, at least in vertebrates a crosstalk has evolved between AMPK
signaling and the Cr/CK system (Neumann et al. 2003 ; Ju et al. 2012 ). Although
AMPK is not directly activated by Cr as postulated earlier (Ponticos et al. 1998 ;
Ingwall 2002 ; Taylor et al. 2006 ), the PCr/Cr ratio will also determine cellular
ATP/ADP ratios via the CK reaction and thus indirectly AMPK activation, as well.
Knockdown of cytosolic CK activates AMPK (Li et al. 2013 ), and similar control of
AMPK signaling is observed when manipulating the cellular levels of adenylate
kinase isoenzymes (Dzeja et al. 2011b ). Such indirect mechanisms may also cause
the additional AMPK activation observed after Cr supplementation in cellular
models of skeletal muscle (Ceddia and Sweeney 2004 ), in the muscles of patients
undergoing exercise programs in different pathological settings (Alves et al. 2012 ),
and in Huntington disease models (Mochel et al. 2012 ), although these findings
need further investigation.
Vice versa, AMPK complexes interact with cytosolic CKs and are able to
phosphorylate them (Ponticos et al. 1998 ; Dieni and Storey 2009 ). Since this does
not affect CK enzyme activity, at least in rodents (Ingwall 2002 ; Taylor et al. 2006 )
this phosphosphorylation remained enigmatic. Our most recent unpublished data
indicate that BB-CK phosphorylation by AMPK may determine subcellular locali-
zation of this enzyme which is known to partially associate with ATP-requiring
cellular structures and ATPases. In myocytes, active AMPK may also increase
cellular Cr uptake by positively acting on Cr transporter (Alves et al. 2012 ; Darrabie
et al. 2011 ), while an inverse effect was found in kidney epithelial cells
(Li et al. 2010 ). If the latter cells are under energy stress, either physiological or
pathological, this mechanism would prevent them to spend additional energy
required for Cr uptake from the glomerular filtrate.
11.5.5 Network Connectivity: AMPK Output Signals and
Downstream Regulation
AMPK integrates a large number of signals from inside and outside the cell that
carry information on the nutrient and energy state from the cellular to organism
level with the aim to mount a coordinated response (Fig. 11.13 ). This response
includes compensation for ATP loss by stimulating catabolic and inhibiting several
anabolic pathways, but also control of many other energy-related biological
checkpoints in cell growth and proliferation, cell motility and polarity, apoptosis,
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