Following an inducing signal of unknown type, and in a burst of activity, oligodendrocytes (OLGs) form myelin; thereafter, they maintain it. OLGs are capable or remyelinating central nervous system axons after a demyelinating injury, implying a capacity to respond a second time to a myelin-inducing signal. In preliminary studies we have found that cultured OLGs express a voltage- dependent outward current that has an inactivating/transient component and a non-inactivating or steady state component. In addition, these cells develop an inward rectifier current after a week in culture. The magnitude of these currents are modified with time/attachment in culture, as is myelin metabolism. The cultured OLG system offers the opportunity to investigate the relationship between the signal for myelin synthesis and ionic current modulation. We will use whole-cell and single channel techniques to identify and characterize further the ionic currents of OLGs investigating the relationship between ionic current modulation and myelin reformation. Studies of ion channels will be carried out on single cells as well as on isolated membrane patches in order to obtain a molecular picture of the mechanisms of ion channel involvement in demyelinating disease. The outward K+ current of OLGs are similar to the voltage-gated K+ currents that have been described for the T lymphocyte. Modulation of the electrical properties of both OLGs and lymphocytes may provide a mechanistic basis for the failure of remyelination and for the abnormalities of immune regulation observed in MS. We will characterize the effects of protein phosphorylation on whole-cell K+ currents using agents known to modulate myelin secretion in OLGs. We will study the sensitivity of the K+ currents to neuropeptides, neurotransmitters, lymphokines, interferons surface adhesion molecules, and purified fractions of MS CSF. We will examine whether these factors are capable of producing transient increases in (Ca++)i using the calcium sensitive dye Fura-2. We will characterize the electrophysiological changes that accompany the transformation of T cells as well as OLGs from the normal to the pathological state. We will study the difference in ionic current activation or expression in T cell lines from control as well as progressive MS patients.
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