Normalization of Ca²⁺ Homeostasis Does not Lead to Correction of Intracellular pH in Hippocampal Culture Neurons under the Influence of Ammonium Ions

In pathologies associated with excitotoxicity and impaired calcium homeostasis, hyperexcitation of neurons is often observed, including during ischemic stroke, hyperammonemia, and neurodegenerative diseases. In the case of long-term sustained depolarization, this hyperactivity disrupts many processes, including the energy balance of ATP, and can lead to cell death. These reactions are often accompanied by prolonged acidification of the cytosol. It affects the activity of a large number of ion channels dependent on intracellular pH, other molecular objects that regulate the concentration of [Ca²⁺], and other ions in the cell, as well as the membrane potential. Such processes may additionally lead to hyperexcitation and disruption of ion homeostasis. Understanding the relationship between [Ca²⁺] and pH, is important for the development of methods to eliminate these dysfunctions. In particular, it remains unclear whether correction of Ca²⁺ homeostasis entails normalization of pH. In this work, it was shown that the elimination of hyperexcitation manifestations, namely, the ultra-high frequency of [Ca²⁺] pulses and the elevated level of basal [Ca²⁺], by using the dopamine D2-like receptor (D2-like) agonist PD-168077 (10 μM) or the α2-adrenergic receptor agonist guanfacine (10 μM) does not lead to a noticeable correction of pH, in hippocampal neurons and astrocytes. Thus, to eliminate the effects of hyperexcitation, pH regulation is a separate task, independent of approaches to normalize calcium homeostasis.

hyperammonemia, intracellular pH, neuronal hyperexcitation, α2-adrenergic and dopamine D2-like receptors, intracellular Ca²⁺