Ion channels and transporters in microglial function in physiology and brain diseases

Microglial cells interact with all components of the central nervous system (CNS) and are increasingly recognized to play essential roles during brain development, homeostasis and disease pathologies. Functions of microglia include maintaining tissue integrity, clearing cellular debris and dead neurons through the process of phagocytosis, and providing tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. Changes of microglial ionic homeostasis (Na⁺, Ca²⁺, K⁺, H⁺, Cl^-) are important for microglial activation, including proliferation, migration, cytokine release and reactive oxygen species production, etc. These are mediated by ion channels and ion transporters in microglial cells. Here, we review the current knowledge about the role of major microglial ion channels and transporters, including several types of Ca²⁺ channels (store-operated Ca²⁺ entry (SOCE) channels, transient receptor potential (TRP) channels and voltage-gated Ca²⁺ channels (VGCCs)) and Na⁺ channels (voltage-gated Na⁺ channels (Nav) and acid-sensing ion channels (ASICs)), K⁺ channels (inward rectifier K⁺ channels (K_ir), voltage-gated K⁺ channels (K_V) and calcium-activated K⁺ channels (K_Ca)), proton channels (voltage-gated proton channel (Hv1)), and Cl^- channels (volume (or swelling)-regulated Cl^- channels (VRCCs) and chloride intracellular channels (CLICs)). In addition, ion transporter proteins such as Na⁺/Ca²⁺ exchanger (NCX), Na⁺-K⁺-Cl^- cotransporter (NKCC1), and Na⁺/H⁺ exchanger (NHE1) are also involved in microglial function in physiology and brain diseases. We discussed microglial activation and neuroinflammation in relation to the ion channel/transporter stimulation under brain disease conditions and therapeutic aspects of targeting microglial ion channels/transporters for neurodegenerative disease, ischemic stroke, traumatic brain injury and neuropathic pain.