Figure 2.

Ion interactions during seizures. The major ion channels and transporters, which serve as important nodes of interaction between ions are depicted, with arrows highlighting the typical direction of ionic flux. Arrows adjacent to an ion reflect the direction of seizure induced concentration change (see Figure 1). During a seizure, K⁺ efflux via a host of K⁺ channels (red) results in accumulation of extracellular K⁺. The cation-chloride transporter KCC2 (yellow) serves as an important link between the seizure-associated reduction in the transmembrane K⁺ gradient and intracellular Cl⁻ accumulation via GABAA receptors (GABA_ARs) (green). GABA_ARs, which are permeable to both Cl⁻ and ${\text{HCO}}_3^{-}$ connect the regulation of Cl⁻, ${\text{HCO}}_3^{-}$ and pH via carbonic anhydrases which catalyze the reversible reaction of H₂O and CO₂ to ${\text{HCO}}_3^{-}$ and H⁺ (orange). Seizures are associated with intracellular acidification which is due, in part, to the activity of Ca²⁺/H⁺ ATPase as it imports H⁺ and extrudes Ca²⁺ in attempt to restore baseline Ca²⁺ concentrations following activity-induced Ca²⁺ influx (cyan). Na⁺/Ca²⁺ exchangers (NCX, pink) connect Ca²⁺ and Na⁺ concentration. Seizure-associated Na⁺ influx via voltage and ligand gated Na⁺ channels (magenta) up regulates the activity of Na⁺/K⁺ ATPases (forest green). Finally, increased intra-neuronal concentrations of Cl⁻, H⁺, Ca²⁺ and Na⁺ all activate K⁺ channels (dashed gray line). The number and complexity of possible ionic interactions highlights the importance of computational models for determining the relevance of these continuously evolving variables, which are often difficult to study experimentally.