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/Kv1.1 | JPN of myelinated axons | Regulate AP propagation and neural excitability | Redistribution to internodes and nodal segments, upregulation | Hyperpolarise axonal Vrest, affect AP threshold, impair AP conduction |
| Microglia, astrocyte (t), OPCs (t) | Proliferation, cell activation | |||
| KCNA2/Kv1.2 | JPN of myelinated axons | Regulate AP propagation and neural excitability | Redistribution to internodes and nodal segments, upregulation | Hyperpolarise axonal Vrest, affect AP threshold, impair AP conduction |
| Reactive astrocyte, microglia, OPC | Proliferation, cell activation | |||
| KCNA4/Kv1.4 | 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/Kv2.1 | 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/Kv2.2 | Soma, proximal dendrites, AIS Not detected in glia |
Influence AP duration during high frequency firing, regulate neuronal excitability | Unknown | Unknown |
| KCNC3/Kv3.3 | Axons, somatodendritic compartment Astrocyte, microglia (t), OPCs (t) |
Regulate AP firing at high frequency | Upregulation in some injured WM axons | Unknown |
| KCND2/Kv4.2 | 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/Kv7.2 | AIS, nodes of Ranvier OPCs, microglia |
Stabilize Vrest, regulate activity of NaV-channels, accelerate AP upstroke, influence neuronal subthreshold excitability, regulate spike generation, and repetitive firing | Unknown | Unknown |
| KCNQ3/Kv7.3 | AIS, nodes of Ranvier Microglia (pro-inflammatory), OPCs, astrocyte (t) |
Stabilize Vrest, regulate activity of NaV-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/Kv7.5 | Soma, dendrites Astrocyte, OPCs, microglia |
Contributes to AHP currents in the HP | Unknown | Unknown |
| KCNV1/Kv8.1 | Unknown Oligo lineage (t) |
Co-assemble with Kv2.1, reduce Kv2.1 current density which may lead to AP broadening and hyper-synchronized high-frequency firing | Unknown | Unknown |
| KCNS2/Kv9.2 | Unknown Oligo lineage (t) |
Co-assemble with Kv2.1 | Unknown | Unknown |
| KCNH5/EAG2 | Unknown Astrocyte (t), OPCs (t) |
Unknown | Unknown | Unknown |
| KCNH7/ERG3 | Unknown Astrocyte (t), OPCs (t), microglia (t) |
Dampen excitability, stabilize Vrest | 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 Vrest, 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 Vrest
Contribute to K+ buffering, glutamate clearance |
Unknown | Unknown |
| KCNT1/KNa1.1 | Soma, axons Astrocytes (t) |
Regulate the generation of slow afterhyperpolarization, firing patterns, and setting and stabilizing the Vrest | Unknown | Unknown |
| KCNN3/KCa2.3 | 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/Kir3.2 | Somatodendritic compartment Astrocyte, oligo lineage (t) |
K+-homeostasis, maintenance of Vrest, hyperpolarization, control of AP firing and neuronal excitability, inhibition of excitatory neurotransmitter release | Unknown | Unknown |
| KCNJ16/Kir5.1 | Somatodendritic compartment, dendritic spines Astrocyte, oligo lineage, microglia (t) |
Silent channel when combined with Kir2.1. When combined with Kir4.1, build channels with larger conductance and greater pH-sensitivity. Plays a role in synaptic transmission Chemoreception K+ buffering |
Unknown | Unknown |
| SCN1A/Nav1.1 | 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/Nav1.2 | 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/Nav1.3 | 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/Nav1.6 | 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/Nav1.9 | 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/CaV1.2 | 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/CaV1.3 | 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/CaV2.1 | 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/CaV2.3 | Dendritic spines, axonal terminals Astrocyte, oligodendrocyte |
Neurotransmitter release, synaptic plasticity, regulation of BK, SK, and KV4.2 channels | Unknown | Unknown |
| CACNA1G/CaV3.1 | 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/CaV3.2 | 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/CaV3.3 | 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 GABAAR-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 |
AHP, afterhyperpolarization; AIS, axon initial segment; AP, action potential; BK, big-conductance Ca2+-activated K+-channels; ER, endoplasmatic reticulum; GABAAR, 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; Vrest, resting membrane potential.