Intracellular pH Regulation in Epileptic Neuronal Activity
Summary
Intracellular pH (pHi) is a critical determinant of neuronal excitability, influencing the function of ion channels, neurotransmitter receptors and metabolic enzymes. In epilepsy, rapid shifts in pHi accompany seizure initiation and propagation: transient alkalinisation can enhance NMDA receptor‐mediated currents and spike generation, whereas acidosis exerts a protective inhibitory feedback. Neurons maintain pHi via coordinated activity of sodium–hydrogen exchangers, bicarbonate–chloride exchangers, monocarboxylate transporters and carbonic anhydrase isoforms, all of which respond to acid–base disturbances arising from CO₂ fluctuations, glycolytic flux and ion flux during synaptic transmission. Emerging work has also identified proton‐sensing G protein‐coupled receptors and mitochondrial buffering pathways as modulators of seizure thresholds. Pharmacological targeting of these mechanisms—including the long-standing use of carbonic anhydrase inhibitors—demonstrates the translational potential of pH regulation in antiepileptic strategies, while novel transporter and receptor modulators are under active investigation.
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Intracellular pH Regulation in Epileptic Neuronal Activity publication trend
The graph below shows the total number of articles in intracellular ph regulation in epileptic neuronal activity across all publications each year (not limited to Nature Index journals).
Technical terms
Intracellular pH (pHi): The concentration of hydrogen ions inside a cell, determining its acid–base balance.
Sodium–hydrogen exchanger (NHE): A membrane protein that exports H⁺ in exchange for Na⁺ to regulate pHi.
Bicarbonate–chloride exchanger: A transport protein that swaps HCO₃⁻ for Cl⁻ to stabilise cellular pH.
Carbonic anhydrase: An enzyme catalysing the reversible hydration of CO₂ to HCO₃⁻ and H⁺, facilitating rapid pH buffering.
Proton-sensing G protein-coupled receptor (OGR1): A cell-surface receptor activated by extracellular protons, transducing pH changes into intracellular calcium signalling.
References
- Characterization of Na+-linked and Na+-independent Cl-/HCO3- exchange systems in Chinese hamster lung fibroblasts.. Journal of Biological Chemistry (1988).
- A rise in saliva and urine pH in children with SCN1A-related epilepsy: An exploratory prospective controlled study. Frontiers in Neurology (2022).
- CO2chemotransduction in central neurons: role of intracellular pH (pHi) and extracellular pH (pHo). Respiratory Research (2001).
- Calcium release from intracellular stores is involved in mitochondria depolarization after lowering extracellular pH in rat brain synaptosomes. Acta Neurobiologiae Experimentalis (2018).
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