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 284

cytokines
hormones Ca 2+

24

cytosolic ATP consumpon

Rec Ch

PCr Cr Pi mitochondrion

ADP
ATP
synth

matrix ADP Cr

16

ANT

mtCK

AT P AT P PCr

8

AMP

AT P

Metabolic control
of AMPK acvaon

ADP

AT P PCr

0

32 16 0

Total ~P (μmoles g -1 )

ATP-
dep.

Cam
KKβ

CK PP LKB1

AK

AMP ADP Cr

Covalent acvaon
(phosphorylaon)

metabolite fluxes
signaling fluxes
acvaon
inhibion
mitochondrial creane kinase
cytosolic creane kinase
cytosolic adenylate kinase
mitochondrial ATP synthase
ATP-dependent enzymes

-

+

- Akt PKA

-

+

+

mtCK
CK
AK
ATP synth.
ATP-dep.

-

AMPK

Non-covalent acvaon Crosstalk (phosphorylaon)

other
substrates

- catabolic enzymes + nucleus +

or

AMPK
PP
LKB1
CamKKβ

AMP-acvated protein kinase
protein phosphatases
liver kinase B1
calmodulin kinase kinase

+

trans-
cripon
factors

-

anabolic enzymes

ANT
Rec
Ch

adenylate translocase
receptor
channel

Effects on key metabolic enzymes Effects on gene transcripon Other effects

Fig. 11.13 AMPK signaling. Large scheme: Activation of AMPK by intra- and extracellular
metabolic and endocrine signals and major fields of downstream signaling . Activation of AMPK
is determined by upstream kinases (covalent activation by LKB1, CamKK , inhibition by Akt and

PKA) and phosphatases. They mediate mainly extracellular signals carrying, e.g., information on
the energy and nutrient state of the cellular environment and the entire organism (endocrine
signals). Covalent activation also depends on some intracellular parameters (Ca 2+ , possibly also
ROS/RNS). As a second layer of regulation, AMPK is activated by ADP and in particular AMP
(allosteric regulation), both acting as second messengers of cellular energy stress. This signaling is
linked to conversion of nucleotides via the adenylate kinase (AK) and creatine kinase
(CK) reactions. Activated AMPK compensates for ATP loss by accelerating catabolism, inhibiting
anabolism, and further effects on cell motility, growth, proliferation, and others, via regulation of
key enzymes and transcription factors. For further details see text. Insert: Connection of AMPK
signaling and phosphotransfer reactions (CK and AK) (Neumann et al. 2003 ). Global cellular
concentration changes of phosphocreatine [PCr] and adenine nucleotides ([ATP], [ADP] and
[AMP]), inorganic phosphate [Pi], and creatine [Cr], calculated from the reactions of CK, AK,
and a generalized ATPase at decreasing “high-energy” phosphates (corresponding to a transition
from rest to high work-load). Note that with “high-energy” phosphate consumption, [ATP]
remains constant until more than 80 % of the PCr pool is consumed. Only then, there is a transient
increase in [ADP] and finally [AMP] starts to rise dramatically. The exponential rise in [AMP]
makes this nucleotide an ideal second messenger for a lowered cellular energy state. This
simplified model assumes that the CK and AK reactions work at equilibrium (which is unlikely
to be true in vivo) and does not account for specific subcellular localizations of CK and AK

β