Palytoxin and the sodium/potassium pump—phosphorylation and potassium interaction

Abstract

We proposed a reaction model for investigating interactions between K+ and the palytoxin-sodium-potassium (PTX-Na+/K+) pump complex under conditions where enzyme phosphorylation may occur. The model is composed of (i) the Albers-Post model for Na+/K+-ATPase, describing Na+ and K+ pumping; (ii) the reaction model proposed for Na+/K+-ATPase interactions with its ligands (Na+, K+, ATP, ADP and P) and with PTX. A mathematical model derived for representing the reactions was used to simulate experimental studies of the PTX-induced current, in different concentrations for the pump ligands. The simulations allow interpretation of the simultaneous action of Na+/K+-ATPase phosphorylation and K+ on the PTX-induced channels. The results suggest that(i) phosphorylation increases the PTX toxic effect, increasing its affinity and reducing the K+occlusion rate, and (ii) K+ causes channel blockage, increases the toxin dissociation rate and impedes the induced channel phosphorylation, implying reduction of the PTX toxic effect.

Hypothesized diprotomeric enzyme complex supported by stochastic modelling of palytoxin-induced Na/K pump channels

“…The binding of two PTX molecules may occur only if the pump is a diprotomeric complex [14]. Evidence of the pump functioning as a diprotomer has been reported [15] and, furthermore, the experiments described above [5,6] were carried out in conditions where it is possible to consider the existence of pumps functioning as diprotomeric complexes [15].…”

“…In addition, due to the Na + occlusion/deocclusion in the channel not bound by PTX, reaction p7 is responsible for the transitions between high-and low-level activities in the PTX-induced channels. The effect of the Na + binding to an α chain of the diprotomer was also reported [14]. The author observed that the presence of three Na + in one α chain of the pump, forming the substate (K + ) 2 E2:Na + 3 E1, reduces the transition rate of the second protomer to state E1.…”

“…The binding of the first PTX molecule to the diprotomeric complex has higher affinity than the second molecule binding ( β pd1 / α pd1  <  β pd8 / α pd8 ). Therefore, the cooperative protein–protein effect in the diprotomer, which is positive in the case of the ATP binding [14], may be interpreted as negative for the PTX binding. This allows PTX to bind to the pump even at very low concentrations, changing its function and inducing the channels, making its toxic effect more effective.…”

“…The author observed that the presence of three Na + in one α chain of the pump, forming the substate (K + ) 2 E2:Na + 3 E1, reduces the transition rate of the second protomer to state E1. The reaction (K + ) 2 E2(K + ) 2 E2→(K + ) 2 E2:(Na + ) 3 E1 is faster than the reaction (K + ) 2 E2(Na + ) 3 E1→(Na + ) 3 E1:(Na + ) 3 E1 [14]. …”

pH during non-synaptic epileptiform activity—computational simulations

“…The inward movement of two potassium ions and the extrusion of three sodium ions by the Na/K pump, which is the source of its electrogenic effect, was represented by a fictitious ion A + flowing according to the electrochemical gradient. The intra and extracellular ionic concentrations of this ion were determined by equations representing the Albers-Post model (Rodrigues et al 2008(Rodrigues et al , 2009.…”