K+ channel alterations in the progression of experimental autoimmune encephalomyelitis

Abstract

Voltage-gated K+ (Kv) channels play critical roles not only in regulating synaptic transmission and intrinsic excitability of neurons, but also in controlling the function and proliferation of other cells in the central nervous system (CNS). The non-specific Kv channel blocker, 4-AminoPyridine (4-AP) (Dalfampridine, Ampyra®), is currently used to treat multiple sclerosis (MS), an inflammatory demyelinating disease. However, little is known how various types of Kv channels are altered in any inflammatory demyelinating diseases. By using established animal models for MS, Experimental Autoimmune Encephalomyelitis (EAE), we report that expression and distribution patterns of Kv channels are altered in the CNS correlating with EAE severity. The juxtaparanodal (JXP) targeting of Kv1.2/Kvβ2 along myelinated axons is disrupted within demyelinated lesions in the white matter of spinal cord in EAE. Moreover, somatodendritic Kv2.1 channels in the motor neurons of lower spinal cord significantly decrease correlating with EAE severity. Interestingly, Kv1.4 expression surrounding lesions is markedly up-regulated in the initial acute phase of both EAE models. Its expression in glial fibrillary acidic protein (GFAP)-positive astrocytes further increases in the remitting phase of remitting-relapsing EAE (rrEAE), but decreases in late chronic EAE (chEAE) and the relapse of rrEAE, suggesting that Kv1.4-positive astrocytes may be neuroprotective. Taken together, our studies reveal myelin-dependent and -independent alterations of Kv channels in the progression of EAE and lay a solid foundation for future study in search of a better treatment for MS.

Ankyrin-G Directly Binds to Kinesin-1 to Transport Voltage-Gated Na+ Channels into Axons

“…The procedure of cardiac perfusion, tissue fixation and sectioning were previously described (Jukkola et al, 2012; Jukkola et al, 2013). …”

Regulation of neurovascular coupling in autoimmunity to water and ion channels

“…There are a number of K + channels implicated in astrocytes. We recently showed that Kv1.4 is highly upregulated in activated astrocytes within and surrounding lesions in the spinal cord of mice induced with EAE [33]. Kv1.6 expression has been reported in astrocyte culture [125] but does not appear to be altered in reactive astrocytes [126].…”

“…Furthermore, other K + channels, including two-pore and Ca 2+ -sensitive K + channels, are also found in astrocytes [28–32]. Voltage-gated Kv1.4 channels are highly upregulated in activated astrocytes around experimental autoimmune encephalomyelitis (EAE; an animal model of MS) lesions [33], although their functional role in this context remains unclear. Astrocytes can participate in cell-to-cell communication by propagation of Ca 2+ waves [34, 35], which require channel proteins in the plasma membrane and endoplasmic reticulum.…”

Activation of conventional kinesin motors in clusters by shaw voltage-gated potassium channels

“…Coronal sections (40-mm thickness) of mouse cerebellum were cut with a Microm HM550 cryostat (Thermo Scientific, Waltham, MA) and collected on Superfrost Plus microscope slides (FisherScientific, Pittsburgh, PA). Immunostaining and imaging were performed as previously described (Jukkola et al, 2012). The whole images captured with a 406 objective lens were processed for quantification using Metamorph by flattening the background, thresholding the images to include only the 5% highest intensity pixels, and binarizing the image.…”