Roles of Ion Channels in Oligodendrocyte Precursor Cells: From Physiology to Pathology

Abstract

Oligodendrocyte precursor cells (OPCs) are a distinct and dynamic glial population that retain proliferative and migratory capacities throughout life. While traditionally recognized for differentiating into oligodendrocytes (OLs) and generating myelin to support rapid nerve conduction, OPCs are now increasingly appreciated for their diverse and non-canonical roles in the central nervous system (CNS), including direct interactions with neurons. A notable feature of OPCs is their expression of diverse ion channels that orchestrate essential cellular functions, including proliferation, migration, and differentiation. Given their widespread distribution across the CNS, OPCs are increasingly recognized as active contributors to the development and progression of various neurological disorders. This review aims to present a detailed summary of the physiological and pathological functions of ion channels in OPCs, emphasizing their contribution to CNS dysfunction. We further highlight recent advances suggesting that ion channels in OPCs may serve as promising therapeutic targets across a broad range of disorders, including, but not limited to, multiple sclerosis (MS), spinal cord injury, amyotrophic lateral sclerosis (ALS), psychiatric disorders, Alzheimer's disease (AD), and neuropathic pain (NP). Finally, we discuss emerging therapeutic strategies targeting OPC ion channel function, offering insights into potential future directions in the treatment of CNS diseases.

Keywords: central nervous system; ion channel; neurological diseases; oligodendrocyte precursor cells.

Figure 2

Dynamic changes in ion channel expression during oligodendrocyte lineage progression. Oligodendrocyte precursor cells (OPCs, top) and mature oligodendrocytes (OLs, bottom) exhibit distinct ion channel expression profiles, reflecting their functional transitions during differentiation. Ion channels are categorized by ion selectivity and are differentially expressed across developmental stages. In OPCs (left panel), a broad array of ion channels is present, including potassium channels (Kir4.1, Kv1.3, Kv1.4, Kv1.5, and Kv1.6), sodium channels (Nav1.1, Nav1.2, Nav1.3, and Nav1.6), calcium channels (Cav1.2, Cav1.3, Cav2.1, Cav2.2, Cav3.1, and Cav3.2), ligand-gated channels (GABA_AR, AMPAR, NMDAR, and P2XR), and other channels such as sodium–calcium exchangers (NCX1 and NCX3) and chloride channels (CLC2). In contrast, mature OLs (right panel) display a more restricted ion channel repertoire. TTX-sensitive Nav channels show minimal expression in OLs. These stage-dependent shifts in ion channel expression underscore the functional transformation of OPCs from a proliferative and migratory phenotype to a mature, myelinating state.

Figure 1

Schematic representation of oligodendrocyte lineage progression and associated molecular markers. Oligodendrocytes arise from neural stem cells (NSCs) through a well-defined lineage progression, with each stage marked by distinct cellular morphology and stage-specific molecular markers. OPCs express cell surface ganglioside epitope (A2B5), SRY-Box Transcription Factor 9 (SOX9), NG2, and PDGFRα. As they differentiate into pre-myelinating OLs, markers such as cell surface markers (O4), Myelin Regulatory Factor (MYRF), and 2′, 3′-cyclic-nucleotide-phosphodiesterase (CNP) are upregulated. Myelinating OLs express myelin-related proteins such as myelin basic protein (MBP) and myelin-associated glycoprotein (MAG).

Figure 3

Ion channels involved in the physiological functions of OPCs. Ion channels mediate a broad range of physiological functions in OPCs, which can be broadly categorized into two major domains: those involved in oligodendrocyte lineage progression (right, blue panels) and those extending beyond classical lineage functions (left, green panels). On the right, ion channel activity orchestrates key developmental processes, including OPC proliferation, migration, differentiation, and myelination. Representative ion channels implicated in these processes include voltage-gated calcium channels (Cav1.2 and Cav1.3), voltage-gated potassium channels (Kv1.3, Kv1.4, and Kv1.6), inwardly rectifying potassium channels (Kir4.1), chloride channels (CLC-2), sodium channels (Nav1.2), and ligand-gated receptors (GABA_AR, AMPAR, NMDAR, and P2X7R). On the left, emerging evidence suggests that OPCs also engage in non-canonical roles via ion channel-dependent mechanisms, including interactions with neurons, astrocytes, microglia, and the vasculature. These interactions may modulate synaptic activity, neuroimmune signaling, and blood–brain barrier (BBB) integrity. Ion channels such as Kir4.1, Cav1.2, and Cav1.3 have been implicated in these processes, whereas others remain unidentified or poorly characterized (indicated by question marks). OPCs are not merely progenitors of myelinating oligodendrocytes, but also dynamic regulators of CNS homeostasis and pathology through ion channel-mediated mechanisms.