Figure 7

Scheme depicting activation of ion-transporting enzymes in cardiomyocytes during electrochemical coupling and actomyosin contraction. (А) The projection of activation of ion-transporting enzymes on the action potential of cardiomyocytes. (B) Activation of ion-transporting enzymes during the action potential of cardiomyocytes. At rest, the membrane charge is maintained by Na,K-ATPase and Na/Ca exchanger (NCX) enzymes. During stimulation, potential-dependent membrane calcium channels (VGCC) become permeable, calcium enters the cell and activates the ryanodine receptors (RyR2) of the sarcoplasmic reticulum (SR). Calcium released from SR interacts with troponin-myosin complex, which leads to muscle contraction. Calcium released from troponin-myosin complex back to the cytosol activates the Ca-ATPase of the sarcoplasmic reticulum (SERCA2), which begins to pump Ca²⁺ back into the SR, in parallel Ca^2 + is pumped out of the cell via membrane calcium ATPase (PMCA) and NCX. (C) Effect of acute hypoxia on ion-transporting enzymes. Increased ROS production, which occurs soon after the onset of hypoxia, leads to Na,K-ATPase inhibition. Tissue specific α2-subunit Na,K-ATPase which is important for regulating of Ca²⁺ levels is more redox sensitive than ubiquitous α1- subunit. So disturbance of activity of α2-containing isozyme is one of the first events during hypoxia that affect calcium transients. Inhibition of both isoforms of Na,K-ATPase results in Ca²⁺ overload, because the increased level of intracellular Na⁺ reverses NCX activity. Also, oxidative damage of VGCC leads to decline of their permeability and disruption of the Ca²⁺ uptake. ROS increases the open probability of RyR, which leads to excessive Ca²⁺ efflux into the cytosol from sarcoplasmic reticulum. PMCA and SERCA are also redox sensitive enzymes, and hypoxia leads to their inhibition, thus Ca²⁺ can not be driven out of the cell.