Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function?

doi:10.3389/fncel.2021.685703

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Front Cell Neurosci. 2021; 15: 685703.

Published online 2021 Jun 25. doi: 10.3389/fncel.2021.685703

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Table 3

Expression and role of unique dysregulated ion channels in experimental models of MS.

Gene/protein	Distribution, localization	Cellular functions during physiological conditions	WM in MS models
			Alterations	Role
KCNA1/K_v1.1	JPN of myelinated axons	Regulate AP propagation and neural excitability	Redistribution to internodes and nodal segments, upregulation	Hyperpolarise axonal V_rest, affect AP threshold, impair AP conduction
	Microglia, astrocyte (t), OPCs (t)	Proliferation, cell activation
KCNA2/K_v1.2	JPN of myelinated axons	Regulate AP propagation and neural excitability	Redistribution to internodes and nodal segments, upregulation	Hyperpolarise axonal V_rest, affect AP threshold, impair AP conduction
	Reactive astrocyte, microglia, OPC	Proliferation, cell activation
KCNA4/K_v1.4	Axons (HP)	Regulate AP propagation and neural excitability	Upregulation in astrocytes and OPCs around EAE lesions	Deficiency ameliorated EAE course in KO mice, but have no effect on demyelination/remyelination in the cuprizone model
	Reactive astrocyte, OPCs	Proliferation
KCNB1/K_v2.1	Soma, proximal dendrites, AIS Microglia, OPCs (t)	Influence AP duration during high frequency firing, regulate neuronal excitability	Unknown in WM Downregulation in motor neurons of GM spinal cord during EAE	Unknown
KCNB2/K_v2.2	Soma, proximal dendrites, AIS Not detected in glia	Influence AP duration during high frequency firing, regulate neuronal excitability	Unknown	Unknown
KCNC3/K_v3.3	Axons, somatodendritic compartment Astrocyte, microglia (t), OPCs (t)	Regulate AP firing at high frequency	Upregulation in some injured WM axons	Unknown
KCND2/K_v4.2	Soma, dendrites Astrocyte (t), OPCs (t), microglia (t)	Regulate threshold for AP initiation and repolarization, frequency-dependent AP broadening, AP back-propagation	Unknown	Unknown
KCNQ2/K_v7.2	AIS, nodes of Ranvier OPCs, microglia	Stabilize V_rest, regulate activity of Na_V-channels, accelerate AP upstroke, influence neuronal subthreshold excitability, regulate spike generation, and repetitive firing	Unknown	Unknown
KCNQ3/K_v7.3	AIS, nodes of Ranvier Microglia (pro-inflammatory), OPCs, astrocyte (t)	Stabilize V_rest, regulate activity of Na_V-channels, accelerate AP upstroke, influence neuronal subthreshold excitability, regulate spike generation and repetitive firing	Unknown in WM Upregulated in demyelinated neocortical axons of L5 pyramidal neurons in the cuprizone model.	Unknown in WM Ensure AP conduction in demyelinated GM axons, decrease excitability
KCNQ5/K_v7.5	Soma, dendrites Astrocyte, OPCs, microglia	Contributes to AHP currents in the HP	Unknown	Unknown
KCNV1/K_v8.1	Unknown Oligo lineage (t)	Co-assemble with K_v2.1, reduce K_v2.1 current density which may lead to AP broadening and hyper-synchronized high-frequency firing	Unknown	Unknown
KCNS2/K_v9.2	Unknown Oligo lineage (t)	Co-assemble with K_v2.1	Unknown	Unknown
KCNH5/EAG2	Unknown Astrocyte (t), OPCs (t)	Unknown	Unknown	Unknown
KCNH7/ERG3	Unknown Astrocyte (t), OPCs (t), microglia (t)	Dampen excitability, stabilize V_rest	Unknown	Unknown
KCNH8/ELK1	Unknown OPCs (t)	Unknown	Unknown	Unknown
KCNK2/TREK1	Axons, and node of Ranviers in afferent myelinated nerve Astrocyte, microglia (t) OPCs (t)	Contribute to “leak” K⁺-current, help establishing and maintaining V_rest, regulate neuronal excitability, ensure AP repolarization at nodes of Ranvier in afferent myelinated fibers Contribute to passive membrane K⁺ conductance, glutamate release	Unknown	Deficiency aggravates EAE course in KO mice Channel activation reduces CNS immune cell trafficking across BBB and attenuate EAE course
KCNK10/TREK2	Unknown Astrocyte OPCs (t)	Contribute to “leak” K⁺-current, help establishing and maintaining V_rest Contribute to K⁺ buffering, glutamate clearance	Unknown	Unknown
KCNT1/K_Na1.1	Soma, axons Astrocytes (t)	Regulate the generation of slow afterhyperpolarization, firing patterns, and setting and stabilizing the V_rest	Unknown	Unknown
KCNN3/K_Ca2.3	Dendrites, AIS Astrocyte, microglia, oligo lineage (t)	Regulate AP propagation and neuronal excitability, contribute to maintaining Ca²⁺-homeostasis K⁺ buffering in astrocytes Microglia proliferation and cytokines production	Unknown	Unknown
KCNJ6/K_ir3.2	Somatodendritic compartment Astrocyte, oligo lineage (t)	K⁺-homeostasis, maintenance of V_rest, hyperpolarization, control of AP firing and neuronal excitability, inhibition of excitatory neurotransmitter release	Unknown	Unknown
KCNJ16/K_ir5.1	Somatodendritic compartment, dendritic spines Astrocyte, oligo lineage, microglia (t)	Silent channel when combined with K_ir2.1. When combined with K_ir4.1, build channels with larger conductance and greater pH-sensitivity. Plays a role in synaptic transmission Chemoreception K⁺ buffering	Unknown	Unknown
SCN1A/Na_v1.1	Somatodendritic compartment, AIS, nodes of Ranvier Microglia, astrocyte, OPCs (t)	Saltatory conduction, maintenance of sustained firing, control of excitability Microglia phagocytosis, cytokine release	Increase or no change; localize along the demyelinated regions	Unknown
SCN2A/Na_v1.2	AIS, immature nodes of Ranvier, along the non-myelinated axons Astrocyte, pre-oligodendrocytes	Back-propagation of AP into the somatodendritic compartment, may support slow spike propagation Oligo maturation	Increase of diffuse distribution along demyelinated axons in various mouse models; no change in myelin-deficient rat Upregulated in astrocytes during EAE	Unclear. Suggested: preservation of AP propagation, or axonal damage
SCN3A/Na_v1.3	Somatodendritic compartment, along the axons including myelinated fibers Astrocyte oligo lineage (t)	AP initiation and propagation, proliferation and migration of cortical progenitors	No change in the optic nerve	Unknown
SCN8A/Na_v1.6	AIS, nodes of Ranvier; low density on cell soma, dendritic shafts, synapses Astrocyte, microglia oligo (t)	AP initiation and propagation, neuronal excitability	Decrease at the nodes of Ranvier, increase of diffuse distribution along the damaged axons, no change at AIS Upregulated in microglia/macrophages during EAE	May trigger Na⁺ increase in axoplasm, reversal of NCX, and intra-axonal Ca²⁺ overload. Deletion improves axonal health during EAE
SCN11A/Na_v1.9	Soma, proximal processes Negligible in all glial cells (t)	Regulate excitation, control activity-dependent axonal elongation, mediate sustained depolarizing current upon activation of muscarinic receptors	Unknown	Unknown
CACNA1C/Ca_V1.2	Somatodendritic compartment (synaptically, extrasynaptically), axons, axonal terminals (extrasynaptically), pioneer axons during development Astrocyte, oligo lineage, reactive microglia	Synaptic modulation, propagation of dendritic Ca²⁺ spikes, regulation of glutamate receptor trafficking, CREB phosphorylation, coupling of excitation to nuclear gene transcription, modulation of long-term potentiation, neurites growth and axonal pathfinding during development Astrogliosis OPCs development and myelination	Unknown	Unknown. Suggested: Neurodegeneration because L-type VGCCs blockers attenuate mitochondrial pathology in nerve fibers and axonal loss Deletion in astrocyte- reduces cell activation and pro-inflammatory mediators release in the cuprizone model Deletion in OPCs reduced remyelination in the cuprizone model
CACNA1D/Ca_V1.3	Somatodendritic compartment, axonal cylinders Astrocyte, microglia oligo lineage	Pacemaking activity, spontaneous firing, Ca²⁺-dependent post-burst after-hyperpolarization, Ca²⁺-dependent intracellular signaling pathways, regulation of morphology of dendritic spines and axonal arbores Oligodendrocyte-axon signaling, release of pro-inflammatory mediators by microglia	Unknown	Unknown. Suggested: neuroprotection because L-type VGCCs blockers attenuate mitochondrial pathology in nerve fibers and axonal loss
CACNA1A/Ca_V2.1	Axonal synaptic terminals, axonal shafts in WM, somatodendritic compartment Reactive astrocyte OPCs, premyelinating oligo, microglia (t)	Neurotransmitter release at neuronal and neuron-glia synapses, regulation of BK and SK channels, control of neuronal firing, regulation of gene expression, local Ca²⁺ signaling, and cell survival Calcium influx in oligo upon neuronal activity	Unknown	Unknown
CACNA1E/Ca_V2.3	Dendritic spines, axonal terminals Astrocyte, oligodendrocyte	Neurotransmitter release, synaptic plasticity, regulation of BK, SK, and K_V4.2 channels	Unknown	Unknown
CACNA1G/Ca_V3.1	Somatodendritic compartment, AIS Astrocyte (t) oligo lineage	Generation and timing of APs, regulation of neuronal excitability, rhythmic AP bursts in thalamus, neuronal oscillations, neurotransmitter release	Unknown	T-cells from KO mice show decreased cytokine release Deficiency in KO mice inhibits the autoimmune response in the EAE model
CACNA1H/Ca_V3.2	Somatodendritic compartment, AIS Astrocyte oligo lineage	Generation and timing of APs, regulation of neuronal excitability, rhythmic AP bursts in thalamus, neuronal oscillations, neurotransmitter release	Unknown	Unknown
CACNA1I/Ca_V3.3	Somatodendritic compartment	Generation and timing of APs, regulation of neuronal excitability, rhythmic AP bursts in thalamus, neuronal oscillations, neurotransmitter release	Unknown	Unknown
RyR2	Along ER (also in axons) Astrocyte, oligo lineage	Ca²⁺ release from the ER into the cytoplasm, vesicle fusion, neurotransmitter release, synaptic plasticity, growth cone dynamics	Unknown	Unknown
RyR3	Along ER (also in axons) Astrocyte, OPCs, oligodendrocytes	Ca²⁺ release from the ER into the cytoplasm, vesicle fusion, neurotransmitter release, synaptic plasticity, growth cone dynamics Astrocyte motility OPCs development	Unknown	Unknown
TRPV1	Soma, post-synaptic dendritic spines, synaptic vesicles Astrocyte, microglia, oligodendrocytes	Regulation of Ca²⁺-signaling, synaptic plasticity Astrocyte: migration, chemotaxis, activation during stress, inflammasome activation Microglia: migration, cytokine production, ROS generation, phagocytosis, polarization, cell death	Suggested a main role in regulating microglia inflammatory response	Both detrimental and beneficial effects have been described in EAE disease
TRPV6	Unknown Astrocyte (t)	Unknown	Unknown	Unknown
TRPM2	Soma and neurites in neuronal cultures Microglia, astrocyte (t), oligodendrocyte (t)	Contribute to synaptic plasticity and play an inhibitory role in neurite outgrowth Microglia activation and generation of proinflammatory mediators	Upregulated in monocyte-lineage cells	TRPM2 deficiency reduce monocyte infiltration in EAE
PKD2/TRPP1	ER, primary cilia, and plasma membrane Astrocyte (t), microglia (t), oligo lineage (t)	Maintenance of Ca²⁺-homeostasis, cell proliferation	Unknown	Unknown
PKD2L2/TRPP3	Unknown Astrocyte (t), microglia (t)	Unknown	Unknown	Unknown
CLCN2/CLC-2	Plasma membranes, intracellular membranes Astrocyte, OPCs, microglia	Maintenance of low intracellular Cl⁻ level, control of cell volume homeostasis, regulation of GABA_AR-mediated synaptic inputs, regulation of neuronal excitability Interacts with AQP4 in astrocytes, regulates OPCs differentiation, contribute to volume regulation and phagocytosis in microglia	Unknown	Unknown
CLCN7/CLC-7	Lysosomes Microglia, astrocyte (t), oligo lineage (t)	Suggested function in the neuronal endo-lysosomal pathway Regulate lysosomal acidification in activated microglia	Unknown	Unknown
GJA4/CX37	Largely expressed in vascular cells	Regulate vasomotor activity, endothelial permeability, and maintenance of body fluid balance	Unknown	Unknown
PANX1/Px1	Soma, dendrites, axons Astrocyte, OPCs microglia	Paracrine and autocrine signaling, ATP-sensitive ATP release in complex with P2X₇Rs, intercellular propagation of Ca²⁺-waves, cell differentiation, migration, synaptic plasticity, memory	Unknown	Panx-1 induced ATP release and inflammasome activation contribute to WM damage during EAE Inhibition of Panx1 using pharmacology or gene disruption delays and attenuates disease course in EAE and cuprizone model
CATSPERG	Unknown Oligo lineage (t) Microglia (t)	Unknown	Unknown	Unknown
CATSPERE	Unknown	Unknown	Unknown	Unknown

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AHP, afterhyperpolarization; AIS, axon initial segment; AP, action potential; BK, big-conductance Ca²⁺-activated K⁺-channels; ER, endoplasmatic reticulum; GABA_AR, ionotropic gamma aminobutyric acid A receptor; HP, hippocampus; JPN, juxtaparanodal regions; NCX, Na⁺/Ca²⁺ exchanger; SCI, spinal cord injury; SK, small-conductance Ca²⁺-activated K⁺-channels; SSCx, somatosensory cortex; t, transcipts; V_rest, resting membrane potential.