ION CHANNELS IN DEMYELINATING DISEASES
Overview
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. In MS, conduction failure along demyelinating disease of the CNS. In MS, conduction failure along demyelinating axons occurs frequently. Broad spectrum K+ channel blockers such as 4-aminopyridine (4-AP) have been funded to facilitated conduction in MS but the effects of 4-AP on oligodendroglial (OLG) survival, regeneration and remyelination are unclear. We found that OLGs and OLG progenitor (OP) cells express a 4- AP sensitive delayed rectifier (Ik) which is encoded for the most part by Kv1.5 gene. Ik has an important role in the regulation of OP proliferation. Recent data from other investigators suggest that Ik is also implicated in neuronal apoptosis. These facts leads to the overall goal of this proposal: To delineate the role of K+ channels in OLG degeneration and regeneration using in-vitro and in-vivo systems with the hope of developing a rational drug design involving K+ channels in demyelinating diseases. We hypothesize that: 1) Up regulation of Ik leads to an intracellular environment that is permissive for OP proliferation or for OP apoptosis depending on the nature of concomitant signals; and 2) Ik is required for sequential activation of cell cycle proteins and regulation of mitogen-activated protein kinases. Patch-clamp techniques, Western blot analysis, and gene transfection experiments will be used to test the above hypothesis. In addition, we will investigate the effect of 4- AP on OLG regeneration and remyelination in the cuprizone animal model where both the extent of demyelination are predictable. Insight from our proposed experiments and knowledge gained from molecular characterizing of K+ channels in axons and glia will hopefully lead to the development of novel K+ channel antagonists selective for axonal Kv channels that will improve impulse conduction in MS at the same time sparing OP cells/OLGs. In addition, there may be ways to promote remyelination using the K+ channels of OP cells/OLGs as drug targets.
Biography
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