PDGF upregulates delayed rectifier via Src family kinases and sphingosine kinase in oligodendroglial progenitors

Abstract

An increase in the expression of the delayed rectifier current ( I K) has been shown to correlate with mitogenesis in many cell types. However, pathways involved in the upregulation of I K by growth factors in oligodendroglial progenitors (OPs) have not been well-elucidated. In this study, we found that treatment with platelet-derived growth factor (PDGF) and basic fibroblast growth factor but not ciliary neurotrophic factor resulted in increased I K density and upregulation of Kv1.5 and Kv1.6 mRNA transcripts. The effect of PDGF on I K was blocked by mimosine, a cell cycle inhibitor, and by genistein, a tyrosine kinase inhibitor. Using inhibitors of PDGF-activated pathways, we found that PDGF-induced upregulation of Kv1.5 and I K density involves Src family tyrosine kinases, sphingosine kinase, and intracellular Ca2+ but not ERK1/2 or phosphatidylinositol 3-kinase pathways. Furthermore, agents that were effective inhibitors of PDGF-induced I Kupregulation also attenuated OP proliferation, supporting the concept that I K is an important link between PDGF-activated signaling cascades and cell cycle progression.

Downregulation of Platelet-Derived Growth Factor-α Receptor-Mediated Tyrosine Kinase Activity as a Cellular Mechanism for K+-Channel Regulation during Oligodendrocyte DevelopmentIn Situ

“…A proportion of white matter NG2 ϩ cells in situ were proliferative, whereas virtually all O4 ϩ cells were postmitotic. These data agree with previous in vitro studies demonstrating a correlation between expression of this channel and proliferative capacity (Gallo et al, 1996;Knutson et al, 1997;Chittajallu et al, 2002;Soliven et al, 2003). However, the fact that white matter O4 ϩ cells identified in this study are nonproliferative but display a significant and measurable I KDR raises an important issue.…”

“…We have shown previously that (1) Kv1.3 and Kv1.5 but not Kv1.4 or Kv1.6 subunit proteins are upregulated by PDGF in OPs in vitro, and (2) selective pharmacological inhibition of Kv1.3 alone elicits cell cycle arrest in proliferating OPs in vitro . It has also been demonstrated that levels of Kv1.5 mRNA are upregulated in cultured OPs after PDGF treatment (Soliven et al, 2003). It is therefore possible that only certain Kv1 subunits (e.g., Kv1.3 and/or Kv1.5) are downregulated during NG2…”

“…The expression of the delayed outward-rectifying K ϩ -channel (K DR ) is linked to cell cycle regulation and hence proliferative capacity because of the following: (1) a downregulation of K DR occurs as oligodendrocyte lineage cells mature (Sontheimer et al, 1989;Barres et al, 1990); (2) proliferative OPs express larger K DR currents (I KDR ) and higher levels of Kv1 subunit expression than cell cyclearrested OPs (Knutson et al, 1997;Chittajallu et al, 2002); (3) pharmacological block of I KDR is sufficient to cause cell cycle arrest (Gallo et al, 1996;Knutson et al, 1997;Ghiani et al, 1999;Schmidt et al, 1999;Chittajallu et al, 2002); and (4) overexpression of specific Kv1 subunits can induce OP proliferation in the absence of mitogens (Vautier et al, 2004). Although the molecular identity of the K DR channel subunits linked to the proliferative capacity of OPs in vitro has been investigated (Attali et al, 1997;Schmidt et al, 1999;Chittajallu et al, 2002;Soliven et al, 2003;Vautier et al, 2004), the actual cellular mechanisms underlying I KDR regulation in an environment closer to the in vivo scenario remain unexplored.…”

Loss of Protein-tyrosine Phosphatase α (PTPα) Increases Proliferation and Delays Maturation of Oligodendrocyte Progenitor Cells

“…Treatment of CG4 cells with the SFK inhibitors SU6656 (2 m and 10 M) or PP2 (2 m and 10 M) resulted in a decrease in the number of cells, suggesting that SFKs are required for CG4 growth (data not shown). This result is similar to previous findings that SFKs are required for PDGFinduced OPC proliferation (45,46).…”

Thematic Review Series: Sphingolipids. Cross-talk at the crossroads of sphingosine-1-phosphate, growth factors, and cytokine signaling*

“…formation and chemotaxis, activation of NADPH oxidase, and increased expression of delayed rectifier current (15,(39)(40)(41). However, whereas cell movement toward PDGF depends on S1P receptor activation, cell survival does not (39).…”