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

https://doi.org/10.1016/j.neuint.2020.104925Get rights and content

Highlights

  • Dynamic microglial ionic homeostasis is important for microglial activation.

  • Ion channels and transporters are involved in regulating microglial function.

  • Dysregulation of ion channels/transporters in microglia contributes to brain pathophysiology.

Abstract

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 (Kir), voltage-gated K+ channels (KV) and calcium-activated K+ channels (KCa)), 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.

Introduction

Microglia, the resident immune cells of the central nervous system (CNS), originate from erythromyeloid progenitor cells in the embryonic yolk sac, migrate into the brain early in the development and then propagate, spread, and ramify throughout the brain parenchyma (Hansen et al., 2018a). Microglia constitute 5–10% of total brain cells in humans (Salter&Stevens, 2017; Li&Barres, 2018) and have been increasingly recognized as central players in CNS health and disease (Salter&Stevens, 2017). In healthy brains, microglia exhibit constant movement of processes to dynamically survey the brain environment for invading organisms, dying neurons, or synapses that need to be removed (Hansen et al., 2018a; Izquierdo et al., 2019). Microglia regulate neurogenesis by exerting trophic function, influencing programmed cell death, establishing and remodeling of neural circuits in the developing brain (Li&Barres, 2018). In response to pathogens or brain lesions, microglia directly extend processes to the regions of damage, engulf and phagocytose cellular debris, apoptotic neurons, or synapses, and generate immune-modulators, including reactive oxygen species (ROS) and cytokines that damage invading organisms, and alter neuronal and immune cell function, respectively (Izquierdo et al., 2019). Microglia also help prune developing synapses and regulate synaptic plasticity and function which provide new insights into how disruptions in microglia-synapse interactions could contribute to synapse loss and dysfunction, and consequently diseases (Hong et al., 2016). Lots of research have focused on changes of genes, such as Arg1, CD206 and iNOS, and changes of cytokines, such as TNF-α, IL-1β and IL-6 in microglial activation, especially during multi-dimensional activation transformation (Boche et al., 2013; Tang&Le, 2016); however, whether changes of intracellular ionic homeostasis and regulatory mechanisms play a role in microglial activation are less studied. Ion channels and transporters are involved in many microglial functions and their expression and function vary with different microglial morphological and functional states (Yu et al., 2015; Izquierdo et al., 2019). In this review, we focus on several major ion channels or transporters which regulate ionic changes, such as Ca2+, K+, Na+, H+ and Cl, relating to microglial functions under physiological and pathophysiological conditions. (see Table 1)

Section snippets

Microglial Ca2+ channels and transporters in physiology

The microglial Ca2+ systems play a critical role in maintaining, handling and modifying the dynamic changes in the cellular Ca2+ levels (Giladi et al., 2016). Several evolutionary conserved molecular cascades are responsible for microglial Ca2+ transport across cellular membranes and intracellular Ca2+ buffering (Kettenmann et al., 2011). Microglial intracellular Ca2+ signals are shaped by electrochemically driven Ca2+ influx through membrane channels and receptors and Ca2+ efflux against the

Microglial K+ channels in physiology

K+ channels are important in microglia since they participate in microglial membrane hyper-polarizations and volume regulation (working together with Cl channels in setting up local osmotic gradients) and thereby in important cellular functions, such as shape changes, phagocytosis, and migration toward chemotaxic stimuli (Nguyen et al., 2017). Patch-clamp studies of microglial cells showed that a wide variety of potassium channels including inward rectifier K+ channels (Kir) (described in rat,

Microglial Cl channels and transporters in physiology

Chloride channels play a vital role in cellular physiology including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, cell proliferation, fluid secretion and regulation of cell volume (Gururaja Rao et al., 2020). Chloride channels expressed in microglia can be classified as members of the volume (or swelling)-regulated Clchannels (VRCCs) and chloride intracellular channels (CLICs) (Table 1 and Fig. 1). VRCCs are of particular importance in

Microglial Na+ channels and transporters in physiology

Sodium channels are essential for cell membrane depolarization to initiate and propagate action potentials in the excitable cells (Mercier et al., 2018). As the non-excitable glia cells, microglia also express voltage-gated sodium channels (Nav) as the main sodium channels to participate in fast-activating/inactivating Na+ currents for regulation of their functions, such as migration, phagocytosis, and secretion of cytokines (Pappalardo et al., 2016) (Table 1 and Fig. 1). Microglia express a

Microglial H+ channels and exchangers in physiology

Regulation of proton current through H+ channels or exchangers mediates local pH change and the removal of positive charge hyperpolarizes the membrane potential. The dominant mechanisms for H+ regulation in microglia include the voltage-gated proton channel (Hv1) and Na+/H+ exchanger (NHE) (Table 1 and Fig. 1), where the Hv1 gene expression is higher relative to NHE1 in microglia (Lam et al., 2013). Hv1 is selectively expressed in microglia but not neurons or astrocytes in the mouse brains (Wu,

Author statement

None.

Declaration of competing interest

None.

Acknowledgements

This work was supported by NIH grants R01 NS048216 (D.S.), R01 NS038118 (D.S.), and VA BLR&D I01 BX004625 (D.S.).

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