Fig. 1.

The influence of pH on neuronal excitability. When extracellular pH (pH_o) is acidic and intracellular pH (pH_i) is alkaline, neuronal excitability is decreased. Upon neuronal stimulation, vesicular release of neurotransmitters, such as glutamate (Glu, blue), is accompanied by the release of co-packaged H⁺. Transient incorporation of the V-ATPase into the plasma membrane induces further expulsion of H⁺ from the cytosol into the synaptic cleft and causes acidic pH_o. The extracellular H⁺ blocks the voltage-gated Ca²⁺ channel (VGCC) and reduces presynaptic Ca²⁺ accumulation, thus inhibiting additional neurotransmitter release and neuronal excitability. Furthermore, acidic pH_o also reduces the opening frequency of postsynaptic NMDA receptors (NMDA_R), thus decreasing postsynaptic excitability. Extracellular ATP (purple) is broken down into adenosine (pink) driven by ecto-ATPase which is stimulated by low pH_o. Adenosine can bind and activate adenosine receptors (A_R) and further decrease neuronal excitability. Neuronal excitability is increased when pH_i is acidic and pH_o is alkaline. The V-ATPase is retrieved from the membrane into early recycling endosomes after neuronal firing, reducing H⁺ extrusion and elevating pH_o. In response to accumulated intracellular Ca²⁺, the pre- and postsynapse plasma membrane Ca²⁺/H⁺ ATPases (PMCA) expel Ca²⁺ and import H⁺, further elevating pH_o. The alkaline pH_o enhances NMDA_R activity, facilitating postsynaptic depolarization. Furthermore, alkaline pH_o inhibits ecto-ATPases and prevents ATP degradation. The increased availability of ATP activates P2X and P2Y receptors, initiating cascades that could enhance neuronal excitability. Many other pH regulatory players discussed in Section 4 (NHEs, AEs, NBCs) may also contribute to neuronal excitability.