Abstract
BackgroundWe have previously demonstrated that PDGF receptor activation indirectly inhibits N-methyl-D-aspartate (NMDA) currents by modifying the cytoskeleton. PDGF receptor ligand is also neuroprotective in hippocampal slices and cultured neurons. PDGF receptors are tyrosine kinases that control a variety of signal transduction pathways including those mediated by PLCγ. In fibroblasts Src and another non-receptor tyrosine kinase, Abelson kinase (Abl), control PDGF receptor regulation of cytoskeletal dynamics. The mechanism whereby PDGF receptor regulates cytoskeletal dynamics in central neurons remains poorly understood.ResultsIntracellular applications of active Abl, but not heat-inactivated Abl, decreased NMDA-evoked currents in isolated hippocampal neurons. This mimics the effects of PDGF receptor activation in these neurons. The Abl kinase inhibitor, STI571, blocked the inhibition of NMDA currents by Abl. We demonstrate that PDGF receptors can activate Abl kinase in hippocampal neurons via mechanisms similar to those observed previously in fibroblasts. Furthermore, PDGFβ receptor activation alters the subcellular localization of Abl. Abl kinase is linked to actin cytoskeletal dynamics in many systems. We show that the inhibition of NMDA receptor currents by Abl kinase is blocked by the inclusion of the Rho kinase inhibitor, Y-27632, and that activation of Abl correlates with an increase in ROCK tyrosine phosphorylation.ConclusionThis study demonstrates that PDGFβ receptors act via an interaction with Abl kinase and Rho kinase to regulated cytoskeletal regulation of NMDA receptor channels in CA1 pyramidal neurons.
Highlights
We have previously demonstrated that platelet-derived growth factor (PDGF) receptor activation indirectly inhibits N-methyl-D-aspartate (NMDA) currents by modifying the cytoskeleton
STI571 is a potent inhibitor of Abelson kinase (Abl) kinase as well as platelet derived growth factor β (PDGFβ) receptors with an IC50 value for Abl in the low micromolar range [27,28]
Active Abl kinase was introduced into the cell via the patch pipette whereas STI571 was added to the ECF
Summary
We have previously demonstrated that PDGF receptor activation indirectly inhibits N-methyl-D-aspartate (NMDA) currents by modifying the cytoskeleton. Long-term potentiation (LTP) and long-term depression (LTD) are forms of plasticity which occur at the synapses between CA3 and CA1 pyramidal neurons of the hippocampus and they underlie some forms of spatial learning and memory [1,2]. Their induction is dependent upon the activation of N-methyl-D-aspartate (NMDA) receptors [3,4]. The NMDA receptor currents must be further enhanced during the high frequency stimulation by the calcium-dependent activation of Pyk and Src kinases in order to induce LTP [5]. A variety of Gα q-coupled receptors stimulate phospholipase C (PLC) β and PKC and enhance NMDA receptors by targeting the Pyk2/Src regulation of NMDA receptors in CA1 neurons [7]
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