Investigating the potassium interactions with the palytoxin induced channels in Na+/K+ pump.
K(+) has been appointed as the main physiological inhibitor of the palytoxin (PTX) effect on the Na(+)/K(+) pump. This toxin acts opening monovalent cationic channels through the Na(+)/K(+) pump. We investigate, by means of computational modeling, the kinetic mechanisms related with K(+) interacting with the complex PTX-Na(+)/K(+) pump. First, a reaction model, with structure similar to Albers-Post model, describing the functional cycle of the pump, was proposed for describing K(+) interference on the complex PTX-Na(+)/K(+) pump in the presence of intracellular ATP. A mathematic model was derived from the reaction model and it was possible to solve numerically the associated differential equations and to simulate experimental maneuvers about the PTX induced currents in the presence of K(+) in the intra- and extracellular space as well as ATP in the intracellular. After the model adjusting to the experimental data, a Monte Carlo method for sensitivity analysis was used to analyze how each reaction parameter acts during each experimental maneuver involving PTX. For ATP and K(+) concentrations conditions, the simulations suggest that the enzyme substate with ATP bound to its high-affinity sites is the main substate for the PTX binding. The activation rate of the induced current is limited by the K(+) deocclusion from the PTX-Na(+)/K(+) pump complex. The K(+) occlusion in the PTX induced channels in the enzymes with ATP bound to its low-affinity sites is the main mechanism responsible for the reduction of the enzyme affinity to PTX.
Rodrigues
Antônio M
AM
Biomedical Engineering Department, Federal University of São João del-Rei, São João del-Rei, MG 36301-160, Brazil.
Almeida
Antônio-Carlos G
AC
Infantosi
Antonio F C
AF
Teixeira
Hewerson Z
HZ
Duarte
Mário A
MA
D000178:Acrylamides / Q000494:pharmacology*; D003064:Cnidarian Venoms; D008962:Models, Theoretical; D011188:Potassium / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D000254:Sodium-Potassium-Exchanging ATPase / Q000096:biosynthesis*; D000095702:Polyether Toxins
D000178:Acrylamides; D003064:Cnidarian Venoms; D011188:Potassium; D000254:Sodium-Potassium-Exchanging ATPase; C010272:palytoxin; D000095702:Polyether Toxins