The astrocytic engine: Na⁺,K⁺-ATPase at the nexus of brain function and malfunction

Astrocytes are fundamental for brain homeostasis and act as dynamic signaling elements within the central nervous system. By maintaining ionic balance, neurotransmitter turnover, and metabolic support, they sustain neuronal excitability and network stability. Ionic excitability of astrocytes is mediated primarily by fluctuations of intracellular Na⁺, K⁺, Ca²⁺, and Cl^- ions. Central to these processes is the Na⁺,K⁺-ATPase, which maintains transmembrane Na⁺ and K⁺ gradients, driving secondary active transport, including uptake of neurotransmitters such as glutamate, γ-aminobutyric acid, and their precursors glutamine and L-serine. Astrocytic Na⁺ changes rapidly coordinate neuronal activity with glial homeostasis via N-methyl-d-aspartate receptor signaling, whereas K⁺ clearance is primarily mediated by the Na⁺,K⁺-ATPase α₂ isoform, preventing neuronal hyperexcitability. The Na⁺,K⁺-ATPase also contributes to neurovascular coupling, linking synaptic activity to local vasodilation through Ca²⁺- and K⁺-dependent signaling in astrocytic endfeet. Beyond ion transport, the Na⁺,K⁺-ATPase serves as a signaling hub, engaging intracellular kinase signaling pathways, including Src and phosphoinositide 3-kinase kinases, thereby modulating astrocyte morphology, metabolism, and stress responses. Dysfunctions of astrocytic Na⁺,K⁺-ATPase isoforms are implicated in multiple neuronal pathologies, including seizures, familial hemiplegic migraine, neurodegeneration, and neuroinflammatory disorders. These pathologies reflect primarily loss-of-function mechanisms, altered ion homeostasis, and reactive oxygen species or inflammatory signaling. Understanding the isoform- and cell-type-specific functions of the Na⁺,K⁺-ATPase across the neurovascular unit will be crucial for future development of targeted therapies aimed to restore ion homeostasis and signaling in the diseased brain.