Ion channels and transporters in microglial function in physiology and brain diseases
Graphical abstract
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 Cl−channels (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.).
References (121)
- et al.
Influence of the vanilloid receptor TRPV1 on the activation of spinal cord glia in mouse models of pain
Exp. Neurol.
(2009) - et al.
Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro
Brain Behav. Immun.
(2013) - et al.
Parkinson's disease: mechanisms and models
Neuron
(2003) - et al.
The L-type voltage-gated calcium channel modulates microglial pro-inflammatory activity
Mol. Cell. Neurosci.
(2015) - et al.
Blockade of chloride channels suppresses engulfment of microspheres in the microglial cell line, BV-2
Brain Res.
(2007) - et al.
Regulation of phagocytosis and cytokine secretion by store-operated calcium entry in primary isolated murine microglia
Cell. Signal.
(2015) - et al.
New insights on the role of microglia in synaptic pruning in health and disease
Curr. Opin. Neurobiol.
(2016) - et al.
Coordinated role of voltage-gated sodium channels and the Na+/H+ exchanger in sustaining microglial activation during inflammation
Toxicol. Appl. Pharmacol.
(2013) - et al.
The anti-parkinsonian drug zonisamide reduces neuroinflammation: role of microglial Nav 1.6
Exp. Neurol.
(2018) - et al.
Involvement of N-type Ca(2+) channel in microglial activation and its implications to aging-induced exaggerated cytokine response
Cell Calcium
(2019)
Ion channels and receptors as determinants of microglial function
Trends Neurosci.
Chloride channel blockers inhibit iNOS expression and NO production in IFNgamma-stimulated microglial BV2 cells
Brain Res.
HYP-17, a novel voltage-gated sodium channel blocker, relieves inflammatory and neuropathic pain in rats
Pharmacol. Biochem. Behav.
NF-kappaB dependent up-regulation of TRPC6 by Abeta in BV-2 microglia cells increases COX-2 expression and contributes to hippocampus neuron damage
Neurosci. Lett.
Topics on the Na+/Ca2+ exchanger: responses of Na+/Ca2+ exchanger to interferon-gamma and nitric oxide in cultured microglia
J. Pharmacol. Sci.
Brain-derived neurotrophic factor (BDNF) induces sustained intracellular Ca2+ elevation through the up-regulation of surface transient receptor potential 3 (TRPC3) channels in rodent microglia
J. Biol. Chem.
Voltage-dependent BK and Hv1 channels expressed in non-excitable tissues: new therapeutics opportunities as targets in human diseases
Pharmacol. Res.
Treadmill exercise ameliorates ischemia-induced brain edema while suppressing Na(+)/H(+) exchanger 1 expression
Exp. Neurol.
Effect of down-regulation of voltage-gated sodium channel Nav1.7 on activation of astrocytes and microglia in DRG in rats with cancer pain
Asian Pac J Trop Med
Post-treatment with oxcarbazepine confers potent neuroprotection against transient global cerebral ischemic injury by activating Nrf2 defense pathway
Biomed. Pharmacother.
N-type voltage-dependent Ca2+ channel in non-excitable microglial cells in mice is involved in the pathophysiology of neuropathic pain
Biochem. Biophys. Res. Commun.
Pre- and post-treatment with novel antiepileptic drug oxcarbazepine exerts neuroprotective effect in the Hippocampus in a gerbil model of transient global cerebral ischemia
Brain Sci.
Members of the chloride intracellular ion channel protein family demonstrate glutaredoxin-like enzymatic activity
PloS One
A critical role of TRPM2 channel in Abeta42 -induced microglial activation and generation of tumor necrosis factor-alpha
Glia
Elevation of basal intracellular calcium as a central element in the activation of brain macrophages (microglia)- suppression of receptor-evoked calcium signaling and control of release function
J. Neurosci.
Elevation of basal intracellular calcium as a central element in the activation of brain macrophages (microglia): suppression of receptor-evoked calcium signaling and control of release function
J. Neurosci.
The ongoing pursuit of neuroprotective therapies in Parkinson disease
Nat. Rev. Neurol.
Repurposed biguanide drugs in glioblastoma exert antiproliferative effects via the inhibition of intracellular chloride channel 1 activity
Front Oncol
Sodium channel activity modulates multiple functions in microglia
Glia
Quantification of the functional expression of the Ca(2+) -activated K(+) channel KCa 3.1 on microglia from adult human neocortical tissue
Glia
Review: activation patterns of microglia and their identification in the human brain
Neuropathol. Appl. Neurobiol.
NCX1 expression and functional activity increase in microglia invading the infarct core
Stroke
Neuropathological stageing of Alzheimer-related changes
Acta Neuropathol.
Vibroacoustic disease
Noise Health
Voltage-gated calcium channels
Cold Spring Harb Perspect Biol
Voltage and pH sensing by the voltage-gated proton channel
HV1. J R Soc Interface
The voltage-gated potassium channel Kv1.3 is required for microglial pro-inflammatory activation in vivo..pdf>
Glia
Protective roles for potassium SK/K(Ca)2 channels in microglia and neurons
Front. Pharmacol.
Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson's disease
Cell Death Dis.
Transient receptor potential channels in microglia: roles in physiology and disease
Neurotox. Res.
IL-4 type 1 receptor signaling up-regulates KCNN4 expression, and increases the KCa3.1 current and its contribution to migration of alternative-activated microglia
Front. Cell. Neurosci.
Structure-functional basis of ion transport in sodium-calcium exchanger (NCX) proteins
Int. J. Mol. Sci.
Store-operated Ca(2+) entry (SOCE) and purinergic receptor-mediated Ca(2+) homeostasis in murine bv2 microglia cells: early cellular responses to ATP-mediated microglia activation
Front. Mol. Neurosci.
K(+) channels: function-structural overview
Comp. Physiol.
Elevated Na/H exchanger 1 (SLC9A1) emerges as a marker for tumorigenesis and prognosis in gliomas
J. Exp. Clin. Canc. Res.
Intracellular chloride channels: novel biomarkers in diseases
Front. Physiol.
Microglia in Alzheimer's disease
JCB (J. Cell Biol.)
Microglia in Alzheimer's disease
J. Cell Biol.
TRPM2 contributes to inflammatory and neuropathic pain through the aggravation of pronociceptive inflammatory responses in mice
J. Neurosci.
Chloride channel blockers suppress formation of engulfment pseudopodia in microglial cells
Cell. Physiol. Biochem.
Cited by (37)
Lead inhibits microglial cell migration via suppression of store-operated calcium entry
2024, Toxicology LettersThe immunometabolic reprogramming of microglia in Alzheimerʼs disease
2023, Neurochemistry InternationalA novel role of lactate: Promotion of Akt-dependent elongation of microglial process
2023, International ImmunopharmacologyEthanol effects on L-type voltage-gated calcium channel performance
2023, Journal of Molecular LiquidsSurface translocation of Kir2.1 channel induces IL-1β secretion in microglia
2022, Molecular and Cellular NeuroscienceCitation Excerpt :An assay of supernatants collected from an MG6 culture solution after 15 min of LPS application showed an increase of inflammatory cytokine IL-1β, which was abolished in the presence of the ML133, which is capable of inhibiting Kir2.x channels. In case of microglia, Kir2.1 channel is the only reported Kir2.x channel and therefore it is likely that ML133 effect shown in this study is mediated by Kir2.1 (Tsai et al., 2013; Luo et al., 2021). This was further confirmed by the transfection of Kir2.1 with the trafficking mutation (deletion mutation of Δ314–315).