CREATINE-CREATINE PHOSPHATE SHUTTLE MODELED AS 2-COMPARTMENT SYSTEM AT DIFFERENT LEVELS OF CREATINE-KINASE ACTIVITY

In order to characterize ADP-ATP and creatine-creatine phosphate (Cr-C rP) shuttles a minimal mathematical model with two compartments and cy clic turnover of matter was designed. The 'mitochondrial' compartment contained 'ATP-synthase' and 'mitochondrial creatine kinase' (mitCK). The 'cytoplasmic' compartment consisted of 'ATPase', 'cytoplasmic crea tine kinase' (cytCK) and an 'ADP-binding structure'. The exchange of m etabolites between these compartments was limited. Different levels of cytCK and mitCK expression as well as different exchange rate constan ts between the compartments were assigned to obtain several different modes. Every steady state obtained in the presence of low ATPase activ ity ('resting' conditions) was then disturbed by a steep activation of ATPase ('muscle performance') and afterwards the transition to a new steady state was followed in time. The ATP-buffering capacity of the s ystem initially acquired by cytCK expression significantly increased a fter additional mitCK supplement. Nevertheless, even the complete Cr-C rP shuttle failed to maintain a high [ATP]/[ADP] ratio during long ter m 'muscle performance' due to the rate limiting CK-transphosphorylatio n in the mitochondria. The facilitated diffusion of Cr and CrP was not critical, and the model worked with the same efficiency even at equal permeabilities for nucleotides and guanidines. Under 'resting conditi ons' the main flux of matter went through the Cr-CrP shuttle, resultin g in 'pumping' of CrP. This ensured a 40 s delay in the [ATP] decrease at 'work'. The partial systems without mitCK were not as effective, a nd this delay was 0-10 s. However, the ADP-ATP shuttle was of more imp ortance at the steady state achieved under 'working' conditions.