C5b-9-activated, K v1.3 channels mediate oligodendrocyte cell cycle activation and dedifferentiation

Abstract

Voltage-gated potassium (K v) channels play an important role in the regulation of growth factor-induced cell proliferation. We have previously shown that cell cycle activation is induced in oligodendrocytes (OLGs) by complement C5b-9, but the role of K v channels in these cells had not been investigated. Differentiated OLGs were found to express K v1.4 channels, but little K v1.3. Exposure of OLGs to C5b-9 modulated K v1.3 functional channels and increased protein expression, whereas C5b6 had no effect. Pretreatment with the recombinant scorpion toxin rOsK-1, a highly selective K v1.3 inhibitor, blocked the expression of K v1.3 induced by C5b-9. rOsK-1 inhibited Akt phosphorylation and activation by C5b-9 but had no effect on ERK1 activation. These data strongly suggest a role for K v1.3 in controlling the Akt activation induced by C5b-9. Since Akt plays a major role in C5b-9-induced cell cycle activation, we also investigated the effect of inhibiting K v1.3 channels on DNA synthesis. rOsK-1 significantly inhibited the DNA synthesis induced by C5b-9 in OLG, indicating that K v1.3 plays an important role in the C5b-9-induced cell cycle. In addition, C5b-9-mediated myelin basic protein and proteolipid protein mRNA decay was completely abrogated by inhibition of K v1.3 expression. In the brains of multiple sclerosis patients, C5b-9 co-localized with NG2 + OLG progenitor cells that expressed K v1.3 channels. Taken together, these data suggest that K v1.3 channels play an important role in controlling C5b-9-induced cell cycle activation and OLG dedifferentiation, both in vitro and in vivo.