Regulation of L-Type Ca++ Currents and Process Morphology in White Matter Oligodendrocyte Precursor Cells by Golli-Myelin Proteins

Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, 90095, USA.
Glia (Impact Factor: 6.03). 08/2010; 58(11):1292-303. DOI: 10.1002/glia.21008
Source: PubMed


The golli myelin basic proteins are expressed in oligodendroglial precursor cells (OPCs) where they play a role in regulating Ca(2+) homeostasis. During depolarization, they influence process outgrowth and migration through their action on voltage-operated Ca(2+) channels (VOCCs). To identify ion channels that are modulated by golli, we examined the electrophysiological properties of VOCCs in OPCs in the white matter of golli knock-out and control mice. OPCs exhibited two distinct Ca(2+) channels, which were distinguished by their voltage dependence and pharmacological profiles and which exhibited many of the hallmarks of LVA/T-type and HVA/L-type Ca(2+) channels. The density of high-voltage-activated (HVA) currents was reduced in OPCs recorded in golli-KO tissue, while low-voltage-activated (LVA) currents remained unaltered in these cells. These data indicate that golli exerts an exclusive influence on L-type Ca(2+) channels in OPCs. Oligodendrocytes (OLs) also displayed LVA and HVA currents, although the density of these currents was much reduced at this developmental stage. These currents were not altered in golli-KO OLs showing the influence of golli on L-type Ca(2+) channels is restricted to a specific time-window during the course of oligodendroglial development. The actions of golli on OPC L-type Ca(2+) channels were accompanied by changes in process morphology, including a reduction in process complexity and the appearance of enlarged varicosities that decorated these cellular processes. These data on L-type Ca(2+) channels and process development provide in situ evidence for the influence of golli on VOCCs, and offer an explanation for the hypomyelination observed in the brains of golli-KO mice.

Download full-text


Available from: Daniel Fulton, Jul 18, 2014
  • Source
    • "The function of these process extensions, and whether they are also apparent on more mature ensheathments awaits further investigation since similar observations are yet to be reported from other time-lapse studies. Varicosities are frequently observed along the processes of immature OL (Fulton et al., 2010). These swellings have been shown to contain enlarged mitochondria (Berger et al., 1991) and may therefore represent foci of enhanced metabolic activity, as S.M. Rassul et al. / Neuropharmacology xxx (2015) 1e11 2 Please cite this article in press as: Rassul, S.M., et al., Live-imaging in the CNS: New insights on oligodendrocytes, myelination, and their responses to inflammation, Neuropharmacology (2015), "
    [Show abstract] [Hide abstract]
    ABSTRACT: The formation and repair of myelin involves alterations in the molecular and physical properties of oligodendrocytes, and highly coordinated interactions with their target axons. Characterising the nature and timing of these events at the molecular and cellular levels illuminates the fundamental events underlying myelin formation, and provides opportunities for the development of therapies to replace myelin lost through traumatic injury and inflammation. The dynamic nature of these events requires that live-imaging methods be used to capture this information accurately and completely. Developments in imaging technologies, and model systems suitable for their application to myelination, have advanced the study of myelin formation, injury and repair. Similarly, new techniques for single molecule imaging, and novel imaging probes, are providing opportunities to resolve the dynamics of myelin proteins during myelination. Here, we explore these developments in the context of myelin formation and injury, identify unmet needs within the field where progress can be advanced through live-imaging approaches, identify technical challenges that are limiting this progress, and highlight practical applications for these approaches that could lead to therapies for the protection of oligodendrocytes and myelin from injury, and restore myelin lost through injury and disease.
    Preview · Article · Sep 2015 · Neuropharmacology
  • Source
    • "irm the effect of UDP - glucose in inhibiting Ca 2þ influx through L - type VOCCs observed in Ca 2þ imaging experi - ments . Data in the literature demonstrate that OPs , either in culture ( Blankenfeld et al . , 1992 ; Kettenmann et al . , 1991 ; Verkhratsky et al . , 1990 ; Williamson et al . , 1997 ) or in brain slices ( Berger et al . , 1992 ; Fulton et al . , 2010 ) , present both T - type and L - type Ca 2þ channels whose expression decreases dur - ing cell maturation ( Berger et al . , 1992 ; Blankenfeld et al . , 1992 ; Verkhratsky et al . , 1990 ) . In order to isolate I Ca in cul - tured OPs , K þ conductances were blocked by dialyzing the cell with a Cs þ - based pipette solution and by ext"
    [Show abstract] [Hide abstract]
    ABSTRACT: In the developing and mature central nervous system, NG2 expressing cells comprise a population of cycling oligodendrocyte progenitor cells (OPCs) that differentiate into mature, myelinating oligodendrocytes (OLGs). OPCs are also characterized by high motility and respond to injury by migrating into the lesioned area to support remyelination. K(+) currents in OPCs are developmentally regulated during differentiation. However, the mechanisms regulating these currents at different stages of oligodendrocyte lineage are poorly understood. Here we show that, in cultured primary OPCs, the purinergic G-protein coupled receptor GPR17, that has recently emerged as a key player in oligodendrogliogenesis, crucially regulates K(+) currents. Specifically, receptor stimulation by its agonist UDP-glucose enhances delayed rectifier K(+) currents without affecting transient K(+) conductances. This effect was observed in a subpopulation of OPCs and immature pre-OLGs whereas it was absent in mature OLGs, in line with GPR17 expression, that peaks at intermediate phases of oligodendrocyte differentiation and is thereafter downregulated to allow terminal maturation. The effect of UDP-glucose on K(+) currents is concentration-dependent, blocked by the GPR17 antagonists MRS2179 and cangrelor, and sensitive to the K(+) channel blocker tetraethyl-ammonium, which also inhibits oligodendrocyte maturation. We propose that stimulation of K(+) currents is responsible for GPR17-induced oligodendrocyte differentiation. Moreover, we demonstrate, for the first time, that GPR17 activation stimulates OPC migration, suggesting an important role for this receptor after brain injury. Our data indicate that modulation of GPR17 may represent a strategy to potentiate the post-traumatic response of OPCs under demyelinating conditions, such as multiple sclerosis, stroke, and brain trauma.
    Full-text · Article · Jul 2013 · Glia
  • Source
    • "The Golli protein isoforms come first developmentally, being expressed in OLGs at intermediate stages of differentiation (Givogri et al. 2001; Tosic et al. 2002; Campagnoni and Campagnoni 2004; Fulton et al. 2010a). There are both karyophilic and plasma membrane-targeted forms, and these proteins promote OLG migration and process extension, and enhance potassium-induced calcium influx via multiple kinase signaling pathways (Paez et al. 2007, 2009a, b, 2010, 2012; Fulton et al. 2010b). The 21.5-kDa MBP isoform is the first of the classic isoforms to be synthesized, starting with OPCs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The classic myelin basic protein (MBP) splice isoforms range in nominal molecular mass from 14 to 21.5 kDa, and arise from the gene in the oligodendrocyte lineage (Golli) in maturing oligodendrocytes. The 18.5-kDa isoform that predominates in adult myelin adheres the cytosolic surfaces of oligodendrocyte membranes together, and forms a two-dimensional molecular sieve restricting protein diffusion into compact myelin. However, this protein has additional roles including cytoskeletal assembly and membrane extension, binding to SH3-domains, participation in Fyn-mediated signalling pathways, sequestration of phosphoinositides, and maintenance of calcium homeostasis. Of the diverse post-translational modifications of this isoform, phosphorylation is the most dynamic, and modulates 18.5-kDa MBP's protein-membrane and protein-protein interactions, indicative of a rich repertoire of functions. In developing and mature myelin, phosphorylation can result in microdomain or even nuclear targeting of the protein, supporting the conclusion that 18.5-kDa MBP has significant roles beyond membrane adhesion. The full-length, early-developmental 21.5-kDa splice isoform is predominantly nuclear-localized due to a non-traditional P-Y nuclear localization signal, with effects such as promotion of oligodendrocyte proliferation. We discuss in vitro and recent in vivo evidence for multifunctionality of these classic basic proteins of myelin, and argue for a systematic evaluation of the temporal and spatial distributions of these protein isoforms, and their modified variants, during oligodendrocyte differentiation. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12195.
    Preview · Article · Feb 2013 · Journal of Neurochemistry
Show more