Figure 4.

Schematic overview of major components and systems that are relevant to neuronal intracellular pH regulation. (A) Main acid extruders comprise monocarboxylate transporters (MCT), Na⁺/H⁺ exchangers (NHE), Na⁺-dependent Cl^-/HCO₃^- -exchanger (NCBE), Na⁺/HCO₃^- -exchanger (NBC), and H⁺-ATPases. Anion exchangers (AE), e.g. Cl^-/HCO₃^- exchanger, act as acid loaders. (B) Intracellular protons mainly result from lactic acid production (glycolysis) and H₂CO₃ formation from metabolic CO₂ production (citrate cycles) involving the mitochondria. Carbonic anhydrases are important for the level of cellular bicarbonate and, thus, for intracellular buffering capacity. (C) Membrane potential indirectly drives transmembane fluxes of H⁺ and bicarbonate. (D) Presynaptic mitochondria are preferentially fueled by lactate and pyruvate to provide ATP, for example, for neurotransmitter re-uptake by vesicular and transmembraneous transporters. (E) The pH gradient across the synaptic vesicle membrane is a driving force for transmitter re-uptake mediated by catecholamine-transporters (CAT), which comprise 5-HT transporters (SERT) dopamine transporters, noradrenaline transporters, GABA-transporters and excitatory acid transporters. As an example, the effect of SERT is shown. Arrows numbered 1–9 point to known targets of the following neuropsychopharmaca (see also Discussion): (1) valproate (Rumbach et al., 1986); (2) levetiracetam (Leniger et al., 2004a); (3) topiramate (Leniger et al., 2004b); (4) moclobemide (Bonnet et al., 2000b); (5) fluoxetine, haloperidol, valproate (Rumbach et al., 1986; Wallace and Starkow, 2000); (6) valproate (Benavides et al., 1982); (7) topiramate, sulthiame (Woodbury and Kemp, 1989; Leniger et al., 2002); (8) tiagabine, topiramate, valproate (Kaila, 1994; Lueckermann et al., 1997; Bonnet et al., 2002); (9) 5-HT re-uptake inhibitors, tricyclics, mirtazapine, venlafaxine (Cao et al., 1997).