Figure 2.

Schematic model for molecular mechanisms underlying aging modulatory effects on NKA isoforms. Aging can either increase the production of ROS, such as superoxide radical and hydrogen peroxide, or induce NO^• release by impairing Ca²⁺ homeostasis and subsequently increasing intracellular Ca²⁺ (nNOS-mediated NO^• production). NO^• is a free radical and can generate peroxynitrite, which may cause neurotoxicity by lipid peroxidation, mitochondria disruption, mutations of DNA and proteins, apoptosis and impairment of α1 activity. Strategies that induce NMDA activation can also activate the cGMP pathway, which, in turn, may lead to neuroprotective signaling, partly by upregulating α2 and α3 (cGMP, cyclic GMP; GLU, glutamate; NKA, Na⁺,K⁺-ATPase).