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Abelson tyrosine kinase links PDGFbeta receptor activation to cytoskeletal regulation of NMDA receptors in CA1 hippocampal neurons.

Beazely MA, Weerapura M, MacDonald JF - Mol Brain (2008)

Bottom Line: Intracellular 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.This 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, University of Toronto, ON, Canada. mbeazely@uwaterloo.ca

ABSTRACT

Background: We 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.

Results: Intracellular 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.

Conclusion: This 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.

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Abelson kinase associates with PDGFβ receptors and inhibits NMDA receptor currents in a ROCK-dependent manner. Abelson kinase (Abl) physically associates with PDGFβ receptors, PLCγ, and Src in hippocampal neurons. Upon activation of PDGFβ receptors, Abelson kinase is tyrosine-phosphorylated and dissociates from the receptor. Introduction of Abelson kinase into isolated hippocampal neurons robustly inhibits NMDA receptor currents in a ROCK-dependent manner, possibly through changes in the actin cytoskeleton.
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Figure 5: Abelson kinase associates with PDGFβ receptors and inhibits NMDA receptor currents in a ROCK-dependent manner. Abelson kinase (Abl) physically associates with PDGFβ receptors, PLCγ, and Src in hippocampal neurons. Upon activation of PDGFβ receptors, Abelson kinase is tyrosine-phosphorylated and dissociates from the receptor. Introduction of Abelson kinase into isolated hippocampal neurons robustly inhibits NMDA receptor currents in a ROCK-dependent manner, possibly through changes in the actin cytoskeleton.

Mentions: In cortical neurons, Abl and Arg are required for normal dendritic branching and are activated downstream of integrin receptors [17,20]. The regulation of dentritic spines and synapses are also important for synaptic plasticity in mature neurons, and depends heavily on actin cytoskeleton dynamics [45,46]. In contrast to previous reports suggesting ROCK activity is inversely proportional to Abl activity [23,47,48], treatment of hippocampal slices with PDGF-BB increased ROCK tyrosine phosphorylation. Furthermore, the ROCK inhibitor attenuated Abl-induced decreases in NMDA-evoked currents. These observations show that ROCK is required for Abl-mediated changes in the actin cytoskeleton that leads to inhibition of NMDA currents and that Abl-mediated inhibition of NMDA receptor currents requires RhoGTPase and ROCK signaling (Figure 5). Therefore, in addition to being crucial for neuronal development, Abl kinase regulates NMDA function in mature neurons and links PDGFβ receptor signaling to the actin cytoskeleton. Our results place Abl at an important intersection between alterations in the neuronal cytoskeleton and regulation of NMDA receptors.


Abelson tyrosine kinase links PDGFbeta receptor activation to cytoskeletal regulation of NMDA receptors in CA1 hippocampal neurons.

Beazely MA, Weerapura M, MacDonald JF - Mol Brain (2008)

Abelson kinase associates with PDGFβ receptors and inhibits NMDA receptor currents in a ROCK-dependent manner. Abelson kinase (Abl) physically associates with PDGFβ receptors, PLCγ, and Src in hippocampal neurons. Upon activation of PDGFβ receptors, Abelson kinase is tyrosine-phosphorylated and dissociates from the receptor. Introduction of Abelson kinase into isolated hippocampal neurons robustly inhibits NMDA receptor currents in a ROCK-dependent manner, possibly through changes in the actin cytoskeleton.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2651131&req=5

Figure 5: Abelson kinase associates with PDGFβ receptors and inhibits NMDA receptor currents in a ROCK-dependent manner. Abelson kinase (Abl) physically associates with PDGFβ receptors, PLCγ, and Src in hippocampal neurons. Upon activation of PDGFβ receptors, Abelson kinase is tyrosine-phosphorylated and dissociates from the receptor. Introduction of Abelson kinase into isolated hippocampal neurons robustly inhibits NMDA receptor currents in a ROCK-dependent manner, possibly through changes in the actin cytoskeleton.
Mentions: In cortical neurons, Abl and Arg are required for normal dendritic branching and are activated downstream of integrin receptors [17,20]. The regulation of dentritic spines and synapses are also important for synaptic plasticity in mature neurons, and depends heavily on actin cytoskeleton dynamics [45,46]. In contrast to previous reports suggesting ROCK activity is inversely proportional to Abl activity [23,47,48], treatment of hippocampal slices with PDGF-BB increased ROCK tyrosine phosphorylation. Furthermore, the ROCK inhibitor attenuated Abl-induced decreases in NMDA-evoked currents. These observations show that ROCK is required for Abl-mediated changes in the actin cytoskeleton that leads to inhibition of NMDA currents and that Abl-mediated inhibition of NMDA receptor currents requires RhoGTPase and ROCK signaling (Figure 5). Therefore, in addition to being crucial for neuronal development, Abl kinase regulates NMDA function in mature neurons and links PDGFβ receptor signaling to the actin cytoskeleton. Our results place Abl at an important intersection between alterations in the neuronal cytoskeleton and regulation of NMDA receptors.

Bottom Line: Intracellular 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.This 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, University of Toronto, ON, Canada. mbeazely@uwaterloo.ca

ABSTRACT

Background: We 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.

Results: Intracellular 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.

Conclusion: This 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.

Show MeSH
Related in: MedlinePlus