Metabotropic P2 receptor activation regulates oligodendrocyte progenitor migration and development

Abstract

To gain insights into the role of purinergic receptors in oligodendrocyte development, we characterized the expression and functional activity of P2 receptors in cultured rat oligodendrocyte progenitors and investigated the effects of ATP and its breakdown products on the migration and proliferation of this immature glial cell population. Using Western blot analysis, we show that oligodendrocyte progenitors express several P2X (P2X(1,2,3,4,7)) and P2Y (P2Y(1,2,4)) receptors. Intracellular Ca(2+) recording by Fura-2 video imaging allowed to determine the rank potency order of the P2 agonists tested: ADPbetaS = ADP = Benzoyl ATP > ATP > ATPgammaS > UTP, alpha,beta-meATP ineffective. Based on the above findings, on pharmacological inhibition by the antagonists oxATP and MRS2179, and on the absence of alpha,betameATP-induced inward current in whole-cell recording, P2X(7) and P2Y(1) were identified as the main ionotropic and metabotropic P2 receptors active in OPs. As a functional correlate of these findings, we show that ATP and, among metabotropic agonists, ADP and the P2Y(1)-specific agonist ADPbetaS, but not UTP, induce oligodendrocyte progenitor migration. Moreover, ATP and ADP inhibited the proliferation of oligodendrocyte progenitors induced by platelet-derived growth factor, both in purified cultures and in cerebellar tissue slices. The effects of ATP and ADP on cell migration and proliferation were prevented by the P2Y(1) antagonist MRS2179. By confocal laser scanning microscopy, P2Y(1) receptors were localized in NG2-labeled oligodendrocyte progenitors in the developing rat brain. These data indicate that ATP and ADP may regulate oligodendrocyte progenitor functions by a mechanism that involves mainly activation of P2Y(1) receptors.

P2X7 receptors and Fyn kinase mediate ATP-induced oligodendrocyte progenitor cell migration

“…Moreover, Miyamoto et al showed Fyn expression in primary cultured OPCs by using the technique of RT-PCR [32]. In addition, by using western blot and electrophysiological methods, Agresti et al reported the expression of P2X7 receptors in primary cultured OPCs [12]. Consistent with previous studies, our results also showed that P2X7 receptors and Fyn were co-expressed in cultured OPCs.…”

“…What's more, ATP at 100 μM could induce OPC migration through P2Y1 receptors [12]. The ATP concentration the authors used was much higher than that in the extracellular space under physiological conditions, which is in the nanomolar level [51].…”

“…OPCs express both P2X(1, 2, 3, 4, 7) and P2Y(1, 2, 4, 13) receptors [12,54]. BzATP is also active at other P2 receptors, such as hP2X1, rP2X3, hP2X3, and rP2Y13 receptors [55,52,56].…”

“…Adenosine 5′-triphosphate (ATP) is not only a neurotransmitter [10], but is also involved in cell proliferation [11], migration [12], survival [13], and apoptosis [14]. Extracellular ATP can activate P2 receptors, which include ligand-gated ion channel receptors (P2X receptors) and metabotropic receptors (P2Y receptors) [15].…”

Physiological and pathological functions of P2X7 receptor in the spinal cord

“…In addition, ATP is the predominant (if not the sole) extracellular messenger that mediates calcium waves in astrocytic glial cells [6,7], which are themselves involved in modulating neuronal activity [8][9][10]. ATP not only acts as a neurotransmitter, but it also stimulates cell proliferation and differentiation [11,12]. Furthermore, while ATP-mediated activation of P2X receptors is linked to opening of a cation channel, and thereby either directly or indirectly to the increase of synaptic transmission, its related metabolite adenosine is a potent inhibitor of excitatory transmission via A1 receptor activation.…”