Abelson tyrosine kinase links PDGFbeta receptor activation to cytoskeletal regulation of NMDA receptors in CA1 hippocampal neurons
© Beazely et al. 2008
Received: 14 August 2008
Accepted: 12 December 2008
Published: 12 December 2008
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.
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.
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.
platelet-derived growth factor
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]. These receptors make a relatively minor contribution to the basal excitatory synaptic potential but they are recruited during high frequency stimulation when the depolarizations summate and cause a relief of their block my Mg2+. The NMDA receptor currents must be further enhanced during the high frequency stimulation by the calcium-dependent activation of Pyk2 and Src kinases in order to induce LTP . Src is brought into proximity of the NMDA receptors through its binding to ND2, a protein which serves as a structural and morphological scaffold for the regulation of NMDA receptors by Src . 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 .
NMDA receptors bind directly to a variety of other scaffolding proteins including actin binding proteins . Actin binding proteins link these receptors to the actin cytoskeleton and these protein-protein interactions are regulated by calmodulin binding and the influx of calcium via NMDA receptors such that the activity of these receptors is closely linked to actin cytoskeletal dynamics . This actin anchoring may be permissive for the mechano-sensitivity of NMDA receptors  and is required for the inhibition of NMDA receptors by myosin light chain kinase and F-actin . Therefore, actin cytoskeleton dynamics are pivotal to regulation of NMDA receptors.
LTD of the NMDA receptor-mediated component of the excitatory synaptic postsynaptic currents (epscs) is blocked by inhibition of serine-threonine phosphatases and can be prevented by using agents that stabilize the cytoskeleton in CA1 neurons . We have previously shown that stimulation of the dopamine D2 receptor (a Gαi-coupled receptor) results in transactivation of platelet derived growth factor β (PDGFβ) receptors [12, 13] and in turn PDGFβ receptor activation causes a long-lasting depression of NMDA receptor currents in CA1 neurons [12, 14, 15] that resembles the LTD of NMDA receptor epscs. For example, inhibition of NMDA receptor currents by the PDGFβ receptor is prevented by the serine-threonine phosphatase inhibitor calyculin A and is also dependent on the stability of the actin cytoskeleton [14, 15]. The mechanism(s) whereby PDGFβ receptor signaling modifies the actin cytoskeleton in CA1 neurons to regulate NMDA receptor currents is unknown, however the inhibition does require activation of PLCγ and it is both calcium- and Src-dependent .
In a variety of cell types PDGFβ receptors form a signal complex with PLCγ, Src and a second tyrosine kinase, Abelson (Abl) kinase and downstream signaling is dependent upon interplay between of these enzymes . Abl kinase is implicated in mechanisms of synaptic plasticity, plays a crucial role in growth cone motility, and is involved dendritic branching in developing neurons [17–20]. In Abl and Abl-related gene (Arg) double-knock out mice, the extent of dendritic branching in substantially reduced  and treatment of developing cultured neurons with the Abl inhibitor, STI571, decreases the complexity of neuronal dendritic branching via an increase in RhoA activity  and possible activation of Rho-associated kinase (ROCK) [22–24]. Despite the identification of Abl as an important regulator of several neuronal processes, it remains unclear how Abl is activated in neurons. In several systems, Abl kinases are also required for Rho-family GTPase coupling to the actin cytoskeleton and can reciprocally signal to ROCK . Given the signaling connection between PDGFβ receptors and Abl as well as the evidence of Abl kinase regulation of neuronal signaling and development, we examined the possibility that in CA1 neurons Abl kinase is activated downstream of PDGFβ receptors and that Abl acting with ROCK is responsible for the alterations in actin cytoskeleton that underlie long-term depression of NMDA receptor activity.
Abl kinase inhibits NMDA-evoked currents
Chromosomal translocations involving Abl kinase result in a constitutively active kinase that causes chronic myeloid leukemia . Recently, STI571 (imatinib mesylate, Gleevec™) has been used to successfully treat patients with this form of leukemia. STI571 is a potent inhibitor of Abl kinase as well as 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. STI571 (2.5 μM) completely blocked the inhibition of NMDA currents by Abl kinase (Figure 1D). The inhibition of NMDA currents by Abl returned upon the washout of STI571 from the ECF (Figure 1E). These data show that STI571 inhibits the depression of NMDA currents induced by Abl and that this inhibition is reversible.
PDGF receptors activate Abl in the hippocampus
We have previously demonstrated that both Src kinase and PLCγ are required for the inhibition of NMDA-evoked currents by PDGFβ receptors [14, 29]. PDGFβ receptor activation activates Abl in HEK293 cells in a Src- and PLCγ-dependent manner [30, 31]. PDGF-BB treatment of hippocampal slices enhanced the phosphorylation of both the tyrosine 416 (associated with increased Src activity) and tyrosine 527 (associated with decreased Src activity (Figure 2C) [32, 33]. Consistent with previous studies examining the activation of Abl kinase, CA1 lysates immunoprecipitated with anti-Abl antibodies showed a decrease in the interactions of Abl with PLCγ (Figure 2D) and Src (not shown). Taken together, these results suggest that Abl interacts with PDGFβ receptors, PLCγ, and Src in hippocampal neurons and activation of PDGFβ receptors decreases the association of Abl with these interacting partners as well as causing an increase in the tyrosine phosphorylation of Abl kinase.
PDGF receptor activation decreases the cytoplasmic pool of Abl kinase
The effect of PDGF-BB on the subcellular fractionation of PDGFβ receptors, ROCK, and NR1
Change in localization after PDGF-BB treatment
63 ± 15% a
136 ± 31%
60 ± 12% a
66 ± 30%
125 ± 30%
81 ± 36%
130 ± 30%
Abl inhibition of NMDA currents is blocked by the ROCK inhibitor Y-27632
In the central nervous system, Abl kinase is involved with several crucial physiological processes. However the majority of studies have used transgenic deletions of Abl and/or Arg or small molecule inhibitors of the kinases [20, 21]. Mechanisms of Abl regulation by cell surface receptors and intracellular signaling pathways in neurons remain unclear, and the role of Abl in post-synaptic neuronal signaling, specifically in NMDA receptor regulation, is unknown. We demonstrate that active Abl kinase inhibits NMDA currents in isolated hippocampal neurons. The inhibition of NMDA currents by Abl is completely and reversibly blocked by STI571, an Abl kinase (and PDGFβ receptor kinase) inhibitor. Although Abl and PDGFβ receptors may be inhibited by STI571, we have not previously observed a significant basal activity level of PDGF receptors in hippocampal neurons in previously published reports [12, 13] and unpublished observations.
Several lines of evidence link cell surface receptors to the activation of Abl kinase. The most detailed studies on the regulation of Abl involve the activation of Abl by PDGFβ receptors in fibroblasts [30, 31]. In hippocampal neurons, Abl appears to be regulated by similar mechanisms. Abl associates with PDGFβ receptors, PLCγ, and Src in CA1 hippocampal neurons. Upon treatment of acutely isolated hippocampal slices with PDGF-BB, the association of Abl with each of these proteins is decreased and this coincides with an increase in tyrosine phosphorylation of Abl kinase.
Interestingly, PDGF-BB treatment increased the phosphorylation of Src at both tyrosine 416 (tyrosine phosphorylation here potentiates Src activity) and 527 (tyrosine phosphorylation inhibits Src activity) . Activation of Src kinase via the phosphorylation of tyrosine 416 is associated with a potentiation of NMDA receptor currents and an increase in long-term potentiation [40–42]. However, we have previously demonstrated that application of PDGF-BB inhibits NMDA currents and that this inhibition is Src-dependent . The identification of Abl as a downstream target in hippocampal neurons coupled with the requirement of Src to fully activate Abl after PDGF receptor activation may help reconcile the apparent contradiction in the requirement of Src for an inhibition of NMDA receptor currents by PDGF receptor activation and the direct potentiation of NMDA receptors by Src . Recent work by Veracini et al. have identified least two distinct subcellular pools of Src mediating distinct signaling pathways in NIH 3T3 cells [43, 44]. The increases in tyrosine phosphorylation at both the inhibitory and activation tyrosine residues of Src in the hippocampus suggest the intriguing possibility that two or more pools of Src may be present in neurons as well. One pool interacting with the PDGFβ receptor and leading to a PLCγ/Abl/Src complex that signals to the cytoskeleton via ROCK (with a resulting inhibition of NMDA receptors) and the other pool interacting directly with ND2 and the NMDA receptor complex to enhance NMDA receptor activity during LTP.
PDGF-BB treatment decreased the association of Abl with PDGFβ receptors. Furthermore, PDGF-BB treatment reduced the association of Abl with PLCγ and Src, suggesting that Abl is activated in hippocampal neurons in a manner similar as previously reported in non-neuronal cells. PDGF-BB treatment of hippocampal slices also induced a translocation of Abl from the cytosolic and membrane fraction to the triton-insoluble fraction. Previous studies have suggested that PDGFβ receptor activation ultimately alters NMDA receptor signaling by inducing changes in cytoskeletal dynamics and Abl kinase is linked in several systems to actin dynamics. Similar to extracellular treatment of neurons with PDGF-BB, the inclusion of Abelson kinase in the patch pipette robustly inhibited NMDA-evoked currents in isolated CA1 neurons and this inhibition was blocked by treatment of neurons with the Abl inhibitor STI571 and the ROCK inhibitor, Y-27632. These results suggest that PDGFβ receptors activate Abl kinase in hippocampal neurons and that Abl links PDGFβ receptor signaling to changes in the neuronal cytoskeleton that ultimately lead to changes in NMDA receptor signaling.
Reagents and antibodies
Active Abl kinase (mouse) was purchased from Upstate Biotechnology/Millipore (Belerica, MA). Each lot of active Abl kinase was tested for phosphorylation of a peptide substrate in an in vitro kinase assay (by the manufacturer). Briefly, each lot of Abl kinase had a specific activity (~1750 units/mg) where 1 unit is defined as incorporating 1 nmol phosphate into 50 μM Abltide (EAIYAAPFAKKK) per minute at 30°C in the presence of 100 μM ATP. PDGF-BB was purchased from R&D Systems (Minneapolis, MN, USA). Y-27632 was purchased from Calbiochem (San Diego, CA). NMDA, glycine, and all other chemical reagents were purchased from Sigma (St. Louis, MO, USA). Antibodies used include those raised against PDGFβ receptor (Epitomics, California, USA), Abelson kinase (Sigma), Src (Cell Signaling, Danvers, MDA) and phospho-Y416 and Y527 Src (Biosource, Carlsbad, CA), and phospho-tyrosine antibody (Santa Cruz, La Jolla, CA), and PLCγ, ROCK, and WAV1 (Cell signaling). For the immunoprecipitation of PDGFβ receptors, an agarose-conjugated anti-PDGFβR antibody from Santa Cruz was employed.
Cell isolation and whole-cell recording
CA1 neurons were isolated from hippocampal slices of postnatal day 14–21 Wistar rats as previously described . The extracellular solution was composed of 140 mM NaCl, 1.3 mM CaCl2, 25 mM N-2-Hydroxyethylpiperazine-N'-thanesulfonic acid (HEPES), 33 mM glucose, 5.4 mM KCl, and 0.5 μM tetrodotoxin, and 0.5 μM glycine, with pH of 7.3–7.4 and osmolarity ranging from 320–330 mOsm. Recordings were done at room temperature. The membrane potential was held at -60 mV throughout the recordings and with a voltage step of 10 mV was applied prior to NMDA application to monitor series resistance. Recordings were rejected if a series resistance change greater than 10% was observed. The intracellular solution consisted of 11 mM Ethyleneglycol-bis-(α-amino-ethyl ether) N,N'-tetra-acetic acid (EGTA) as intracellular calcium chelating buffer, 10 mM HEPES, 2 mM MgCl2, 2 mM Tetraethyl ammonium chloride (TEA-Cl) to block K+ channel, 1 mM CaCl2, 140 mM CsF, and 4 mM K2ATP. NMDA currents were evoked by rapid application of NMDA solution delivered from a multi-barreled fast perfusion system for 2 seconds in every minute. The solution was delivered at a rate of approximately 1 ml per minute. Abl or heat-inactivated Abl (0.5 μg/mL) was added to the ICF.
Immunoprecipitation and western blotting
The CA1 region of the hippocampus was microdissected from day 14–22 Wistar rat pups. CA1 slices (5–10 per condition) were incubated for 10 minutes with vehicle or PDGF-BB. Slices were washed in ice-cold ECF and homogenized in solubilization buffer (20 mM Tris, pH = 7.5, 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 30 mM Na pyrophosphate, 1 mM βglycerophosphate, 1% Triton (1% NP-40 was substituted for immunoprecipitation), 1 mM Na3VO4, and MINI cocktail (Roche, Mannheim, Germany). Samples were centrifuged at 14,000 × g for 20 minutes and lysates were used for protein determination. Total protein concentration was determined by BCA Protein Assay (Pierce, Rockford, Il, USA). For Western blot, equal amounts of protein were loaded for each sample. For immunoprecipitations, lysate protein concentrations were normalized and lysates were incubated with primary antibody and protein A/G beads (Sigma) overnight at 4°C. Beads were washed three times and boiled in SDS loading buffer for 5 minutes before separation by SDS page electrophoresis. Proteins were transferred to nitrocellulose membranes, blocked with 5% non-fat dry milk in Tris-buffered saline for 1 hr at room temperature or overnight at 4°C, and incubated in primary antibodies for 1 hr or overnight at 4°C. Membranes were washed three times in Tris-buffered saline with 0.1% Tween-20, incubated with HRP-conjugated secondary antibodies for 1 hr, washed again, and bound antibodies were visualized by the enhanced chemiluminescence method. Densitometric analysis of Western blots was performed using the Kodak Image Station 2000R software.
Hippocampal tissue was incubated with vehicle or PDGF-BB and the tissue was dounce homogenized in fractionation buffer 1 to yield the S1 fraction (buffer 1: 0.32 M sucrose, 4 mM HEPES, pH 7.3, MINI protease inhibitor cocktail 1:10, and 1 mM Na3VO4). The homogenized tissue was centrifuged at 1000 × g for 10 minutes at 4 degrees. The supernatant was retained and centrifuged at 14,000 × g for 20 minutes. The supernatant (S2) was retained and the insoluble material was resuspended in fractionation buffer 2 (buffer 1 + 1% triton). The resuspended mixture was centrifuged at 100,000 × g for 60 minutes and the supernatant (S3, triton-soluble membrane fraction) was retained. The pellet (P3) was resuspended and dissolved in fractionation buffer 3 (buffer 1 + 0.5% SDS + 1% deoxycholate). Protein concentration was determined by BCA protein assay and lysates were subjected to Western blotting as described above.
Statistical analysis of the data was completed using Prism® GraphPad program. Graphs and sample tracings were made from Origin® program. All data was reported as mean ± SEM. Significance level was set at α = 0.05. Data was analyzed by Student's t-test or unpaired Student's t-test where appropriate.
All animal experiments were performed in agreement with the guidelines of the policies on the Use of Animal at the University of Toronto.
This work was supported by a grant to JFM from the Canadian Institutes of Health Research (15514) and a postdoctoral award to MAB. MW received support from the Canadian Heart and Stroke Foundation.
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