Regulation of neuronal PKA signaling through AKAP targeting dynamics

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1 European Journal of Cell Biology 85 (2006) REVIEW Regulation of neuronal PKA signaling through AKAP targeting dynamics Mark L. Dell Acqua a,b,, Karen E. Smith a, Jessica A. Gorski a, Eric A. Horne a, Emily S. Gibson a, Lisa L. Gomez a a Department of Pharmacology, University of Colorado at Denver and Health Sciences Center at Fitzsimons, P.O. Box 6511, Mail Stop 8303, Aurora, CO , USA b Program in Neuroscience, University of Colorado at Denver and Health Sciences Center at Fitzsimons, P.O. Box 6511, Mail Stop 8303, Aurora, CO , USA Abstract Central to organization of signaling pathways are scaffolding, anchoring and adaptor proteins that mediate localized assembly of multi-protein complexes containing receptors, second messenger-generating enzymes, kinases, phosphatases, and substrates. At the postsynaptic density (PSD) of excitatory synapses, AMPA (AMPAR) and NMDA (NMDAR) glutamate receptors are linked to signaling proteins, the actin cytoskeleton, and synaptic adhesion molecules on dendritic spines through a network of scaffolding proteins that may play important roles regulating synaptic structure and receptor functions in synaptic plasticity underlying learning and memory. AMPARs are rapidly recruited to dendritic spines through NMDAR activation during induction of long-term potentiation (LTP) through pathways that also increase the size and F-actin content of spines. Phosphorylation of AMPAR-GluR1 subunits by the camp-dependent protein kinase (PKA) helps stabilize AMPARs recruited during LTP. In contrast, induction of long-term depression (LTD) leads to rapid calcineurin-protein phosphatase 2B (CaN) mediated dephosphorylation of PKA-phosphorylated GluR1 receptors, endocytic removal of AMPAR from synapses, and a reduction in spine size. However, mechanisms for coordinately regulating AMPAR localization, phosphorylation, and synaptic structure by PKA and CaN are not well understood. A kinase-anchoring protein (AKAP) 79/150 is a PKA- and CaN-anchoring protein that is linked to NMDARs and AMPARs through PSD-95 and SAP97 membrane-associated guanylate kinase (MAGUK) scaffolds. Importantly, disruption of PKA-anchoring in neurons and functional analysis of GluR1 MAGUK AKAP79 complexes in heterologous cells suggests that AKAP79/150 anchored PKA and CaN may regulate AMPARs in LTD. In the work presented at the First International Meeting on Anchored camp Signaling Pathways (Berlin-Buch, Germany, October 15 16, 2005), we demonstrate that AKAP79/150 is targeted to dendritic spines by an N-terminal basic region that binds phosphatidylinositol-4,5-bisphosphate (PIP 2 ), F-actin, and actin-linked cadherin adhesion molecules. Thus, anchoring of PKA and CaN as well as physical linkage of the AKAP to both cadherin-cytoskeletal and MAGUK receptor complexes could play roles in coordinating changes in synaptic structure and receptor signaling functions underlying plasticity. Importantly, we provide evidence showing that NMDAR-CaN signaling pathways implicated in AMPAR regulation during LTD lead to a disruption of AKAP79/150 interactions with actin, MAGUKs, and cadherins and lead to a loss of the AKAP and anchored PKA from postsynapses. Our studies thus far indicate that this AKAP79/150 translocation depends on activation of CaN, F-actin reorganization, and possibly Ca 2+ -CaM binding to the N-terminal basic regions. Importantly, this tranlocation of the AKAP79/150 PKA complex from spines may shift the balance of PKA kinase and CaN/PP1 phosphatase activity at the postsynapse in favor of the phosphatases. This loss of PKA could then promote actions of CaN and PP1 during induction of LTD including maintaining AMPAR dephosphorylation, promoting Corresponding author. Department of Pharmacology, University of Colorado at Denver and Health Sciences Center at Fitzsimons, P.O. Box 6511, Mail Stop 8303, Aurora, CO , USA. address: mark.dellacqua@uchsc.edu (M.L. Dell Acqua) /$ - see front matter r 2006 Elsevier GmbH. All rights reserved. doi: /j.ejcb

2 628 ARTICLE IN PRESS M.L. Dell Acqua et al. / European Journal of Cell Biology 85 (2006) AMPAR endocytosis, and preventing AMPAR recycling. Overall, these findings challenge the accepted notion that AKAPs are static anchors that position signaling proteins near fixed target substrates and instead suggest that AKAPs can function in more dynamic manners to regulate local signaling events. r 2006 Elsevier GmbH. All rights reserved. Contents Subcellular organization of signaling pathways by A kinase-anchoring proteins Organization of the postsynaptic density (PSD) of excitatory synapses by scaffold and anchoring proteins Regulation of AMPA receptors by serine/threonine kinases and phosphatases in NMDAR-dependent plasticity AMPAR regulation, actin, cell adhesion molecules and structural plasticity The AKAP79/150 scaffold at the PSD Mechanisms of AKAP79/150 postsynaptic localization and implications for linking structural and functional plasticity Regulation of AKAP79/150 postsynaptic localization by NMDAR signaling pathways implicated in LTD and excitotoxicity 630 Conclusions References Subcellular organization of signaling pathways by A kinase-anchoring proteins Specificity and efficiency in cell signaling can be achieved through assembly of multi-protein complexes by scaffolding, anchoring and adaptor proteins that recruit receptors, second messenger-generating enzymes, kinases and phosphatases, and target substrates to specific subcellular locations (Smith and Scott, 2002). For protein kinase (PKA), A kinase-anchoring proteins (AKAPs) have been characterized that anchor PKA holoenzyme through binding RI or RII regulatory subunits. AKAPs contain a conserved amphipathic helix motif that binds to the N-terminus of R subunit dimers with high affinity. This AKAP PKA complex is then localized through unique targeting domains on the AKAPs to specific locations where it is poised for camp activation (Dell Acqua, 2003). In addition to anchoring PKA, many AKAPs serve as multi-functional signal integrators that bind other signaling, scaffold, and membrane receptor proteins. Importantly, studies have implicated AKAPorganized signaling complexes in ion channel modulation, G-protein-coupled receptor desensitization, vesicular secretion, actin cytoskeletal dynamics, cell division and gene transcription regulated by camp, Ca 2+, and lipid second messengers (Michel and Scott, 2002). Since many of these cellular processes are altered in human disease, understanding the mechanisms of AKAP signaling pathways may aid in the development of novel therapeutics. Organization of the postsynaptic density (PSD) of excitatory synapses by scaffold and anchoring proteins At the postsynaptic membrane of excitatory synapses, PDZ domain-containing scaffold proteins such as PSD- 95, GRIP, Shank and PICK1 combine with other scaffold proteins and cytoskeletal proteins to form a structure called the PSD (Kim and Sheng, 2004). AMPA (AMPAR) and NMDA (NMDAR) glutamate receptors are linked to the actin cytoskeleton and signaling proteins in dendritic spines through this network of PSD proteins. These macromolecular assemblies are thought to play central roles in regulating receptor activity, localization, and synaptic structure in synapse formation during development, synaptic plasticity in learning and memory, and neuronal dysfunction and cell death in neuropathologies. Regulation of AMPA receptors by serine/ threonine kinases and phosphatases in NMDAR-dependent plasticity Many studies have focused on the hippocampus as a model system to understand mechanisms of plasticity in learning and memory as well as excitotoxic neuronal cell damage and loss in stroke and epilepsy. However, much of what has been learned in the hippocampus is relevant for other CNS excitatory circuits. In long-term potentiation (LTP) and depression (LTD) plasticity at hippocampal CA3 CA1 pyramidal cell synapses, NMDAR-Ca 2+ signals modulate synaptic strength through kinases and phosphatases that regulate AM- PAR channel properties and synaptic localization (Malenka and Bear, 2004). Specifically, high-frequency stimulation (HFS) in LTP rapidly increases, while lowfrequency stimulation (LFS) in LTD decreases, synaptic AMPAR activity and number (reviewed in Bredt and Nicoll, 2003; Malenka, 2003; Song and Huganir, 2002). In particular, PKA phosphorylation of Ser845 on the GluR1 subunit increases AMPAR open probability (P o ) and helps stabilize AMPARs recruited to synapses

3 M.L. Dell Acqua et al. / European Journal of Cell Biology 85 (2006) Fig. 1. Organization of AKAP79/150 postsynaptic signaling complexes and regulation of AMPAR phosphorylation and trafficking by PKA and CaN. (A, B) AKAP79/150 can be linked to AMPARs both by SAP97 binding to GluR1 and through PSD-95 interactions with Stargazin/TARPs (not shown). (C) Regulation for GluR1/2 AMPARs is shown. GluR2/3 AMPARs existing in a rapid cycling pool that helps maintain basal transmission are not shown. However, GluR2/3 receptors, while not being PKA substrates, are nonetheless also endocytosed through CaN-dependent pathways during long-term depression. See text for additional details. during LTP through high Ca 2+ stimulation of calciumcalmodulin-dependent protein kinase II (CaMKII)- driven exocytosis (Banke et al., 2000; Esteban et al., 2003; Hayashi et al., 2000; Lee et al., 2003). Additionally, CaMKII phosphorylation of GluR1Ser831 increases single channel conductance in LTP (Fig. 1C) (Bredt and Nicoll, 2003; Malenka, 2003; Song and Huganir, 2002). Conversely, LTD requires dephosphorylation of Ser845 through low Ca 2+ stimulation of CaN and protein phosphatase 1 (PP1) and CaN-dependent endocytic AMPAR removal from synapses through proteins that bind GluR2 subunits (Fig. 1C) (Beattie et al., 2000; Carroll et al., 2001; Lee et al., 1998, 2000, 2002, 2004). Thus, synaptic strength is regulated by NMDAR control of AMPAR phosphorylation and trafficking (Luscher et al., 1999, 2000). AMPAR regulation, actin, cell adhesion molecules and structural plasticity In conjunction with membrane trafficking, lateral exchange between the synaptic and extrasynaptic plasma membrane is also thought to control AMPAR function. Stimulated exocytosis underlying LTP delivers AMPARs to extrasynaptic sites prior to synaptic incorporation (Passafaro et al., 2001). Likewise, sites of clathrindependent endocytosis, involved in AMPAR removal during LTD, are localized adjacent to the PSD on spines (Blanpied et al., 2002). In addition, extrasynaptic AM- PARs are more mobile and more readily endocytosed than synaptic receptors, further suggesting the importance of regulating AMPAR lateral exchange (Ashby et al., 2004; Groc et al., 2004). Thus, to accommodate rapid AMPAR insertion or removal, the physical structure of spines and synapses must also be plastic. Actin is the main cytoskeletal protein in spines, and it is believed that actin dynamics regulate not only spine development and morphology but also plasticity (Fukazawa et al., 2003; Kim and Lisman, 1999; Krucker et al., 2000; Matus, 2000). Indeed, AMPAR recruitment during development and LTP is accompanied by increased spine volume and F-actin polymerization. In contrast, LTD decreases spine volume and actin (reviewed in Lamprecht and LeDoux, 2004; Matsuzaki et al., 2004; Okamoto et al., 2004). These structural changes are interrelated with changes in transynaptic adhesion. In particular, cadherins are homophilic calcium-dependent adhesion molecules linked to the actin cytoskleton by b/a-catenin (cat) complexes that are important in synapse formation, LTP and actin-based structural plasticity (Bozdagi et al., 2000; Huntley et al., 2002; Tanaka et al., 2000; Tang et al., 1998). Postsynaptic cadherin/catenin complexes are linked to F-actin in an adhesion ring surrounding the PSD (Uchida et al., 1996) that may regulate synaptic size and act as a barrier to AMPAR trafficking (reviewed in Choquet and Triller, 2003). Thus, understanding how aspects of structural and functional plasticity are coordinated by PSD protein signaling complexes is an important topic for investigation. The AKAP79/150 scaffold at the PSD AKAP79/150 has emerged as an important postsynaptic membrane scaffold regulating AMPAR

4 630 ARTICLE IN PRESS M.L. Dell Acqua et al. / European Journal of Cell Biology 85 (2006) phosphorylation (Bauman et al., 2004). Human AKAP79 and rat AKAP150 share a high degree of sequence identity and differ mainly in the insert of a 9-amino-acid repeat sequence with no known function that is found only in rodents. Our studies have shown that recruitment of AKAP79/150 to NMDARs and AMPARs is achieved by association with the membrane/ actin cytoskeleton (Gomez et al., 2002) and binding to PSD membrane-associated guanylate kinase (MAGUK) scaffold proteins PSD-95 and SAP97 (Colledge et al., 2000) (Fig. 1A and B). Additionally, AKAP79/150 contains binding sites for PKA-RII subunits (Carr et al., 1992), PKC (Klauck et al., 1996), and CaN catalytic A subunit (CaNA) (Fig. 1A) (Coghlan et al., 1995; Dell Acqua et al., 2002) We recently used fluorescence resonance energy transfer (FRET) microscopy to demonstrate PKA AKAP79 CaN ternary complex assembly with SAP97 at the plasma membrane of living cells (Oliveria et al., 2003). Importantly, we were able to image simultaneous anchoring of PKA-RII and CaNA subunits to AKAP79 within approximately 50 ( A of each other, indicating that the AKAP recruits both the kinase and phosphatase to AMPARs (Fig. 1B). In support of this model, AKAP79 anchored PKA and CaN oppose each other in bi-directional regulation of AMPA-GluR1 currents when reconstituted in heterologous cells (Tavalin et al., 2002; Dell Acqua et al., 2002). In addition, global disruption of AKAP PKA anchoring or inhibition of PKA activity with synthetic peptides in hippocampal neurons leads to a CaNdependent, LTD-like down-regulation of AMPAR currents and loss AMPAR surface expression that likely involves AKAP79/150 (Hoshi et al., 2005; Rosenmund et al., 1994; Snyder et al., 2005; Tavalin et al., 2002). Therefore, the AKAP79/150 complex may also help regulate AMPAR phosphorylation, trafficking, and activity underlying NMDAR-dependent plasticity. Mechanisms of AKAP79/150 postsynaptic localization and implications for linking structural and functional plasticity We have previously shown that AKAP79/150 is localized to the PSD through an N-terminal targeting domain (amino acids 1 153) consisting of three polybasic sub-domains (A, B, C) that bind PIP 2, F-actin, and cadherin adhesion complexes (Fig. 1A and B) (Dell Acqua et al., 1998; Gomez et al., 2002; Gorski et al., 2005). A novel feature of this organization is that the AKAP may link F-actin, PIP 2, MAGUKs and cadherins together, with the actin cytoskeleton as the master scaffold (Fig. 1B). In fact, AKAP79/150 recruitment to MAGUK glutamate receptor complexes depends first on its proper localization to the membrane cytoskeleton and is disrupted by actin polymerization inhibitors (Gomez et al., 2002). Electron microscopy and histochemical studies have shown AKAP79 and cadherins localized within the PSD but also enriched perisynaptically, where cadherins are found in an adhesion ring around the PSD (Sik et al., 2000; Uchida et al., 1996). Positioning MAGUK AKAP79 PKA/CaN complexes in the adhesion ring would provide an optimal geometry for regulating AMPAR phosphorylation. Under basal activity, AKAP anchored PKA is partially active and CaN is inhibited (Tavalin et al., 2002; Dell Acqua et al., 2002). Thus AKAP cadherin complexes might define the boundaries of an area of high PKA and low CaN activity, with PKA acting as a sentry to maintain basal AMPA-GluR1 phosphorylation (Lee et al., 2000) (Fig. 2A). In addition, MAGUK AKAP cadherin catenin complexes might also be part of a physical barrier keeping AMPARs in the synapse. Thus, interaction between AKAP79/150, MAGUKs, and cadherins may coordinate synaptic form and function by linking adhesion complexes with signaling proteins that control AMPAR phosphorylation and trafficking. Regulation of AKAP79/150 postsynaptic localization by NMDAR signaling pathways implicated in LTD and excitotoxicity NMDA treatments that induce LTD and excitotoxicity in cultured neurons cause depolymerization of spine actin, relocalization of AKAP79/150 away from dendritic spines, dephosphorylation of the GluR1-ser845 and endocytosis of AMPA receptors through CaNdependent pathways (Fig. 2B and C) (Beattie et al., 2000; Ehlers, 2000; Halpain et al., 1998; Lin et al., 2000; Gomez et al., 2002). These NMDA treatments also disrupt AKAP79/150 interactions with MAGUKs and cadherins and therefore may remove part of the physical barrier limiting AMPAR diffusion as well as remove PKA from its watchtowers where it keeps synaptic AMPARs phosphorylated (Gomez et al., 2002; Gorski et al., 2005). Indeed, our published and recent unpublished studies (presented at the First International Meeting on Anchored camp Signaling Pathways (Berlin-Buch, Germany, October 15 16, 2005)) have demonstrated that when AKAP79/150 leaves synapses in response to NMDA it takes its anchored pool of PKA with it. We have visualized this movement of the AKAP79 PKA complex in living cells transfected with CFP and YFP-tagged proteins using FRET microscopy. In neurons expressing AKAP79WT-CFP and PKA-RII- YFP we detect enrichment of CFP, YFP and FRET signals in dendritic spines (spine/shaft fluorescence ratios of 1.7). In response to NMDA treatment, AKAP79-CFP, RII-YFP, and FRET signals shift away

5 M.L. Dell Acqua et al. / European Journal of Cell Biology 85 (2006) Fig. 2. Model for role of AKAP79/150 PKA and CaN anchoring and NMDAR targeting regulation in control of AMPAR phosphorylation and endocytosis in long-term depression. See text for details. from spines to the cytoplasm of dendrite shafts (spine/ shaft fluorescence ratios of 0.8). As an important negative control, spine localization of RII-YFP, AKAP79-RII FRET, and regulation of RII-YFP localization in response to NMDA application are all absent in neurons expressing an AKAP79DPKA-CFP mutant that is unable to anchor PKA. In addition, consistent with the AKAP RII interaction remaining constant during movement, normalized FRET values that are proportional to the amount of AKAP PKA complex are not significantly different for entire dendrites of control ( ) and NMDA-treated neurons ( ). Based on these FRET imaging observations, we propose that activation of NMDA receptors during LTD leads to a redistribution of AKAP79/150 and its anchored pool of PKA away from dendritic spines and the PSD. Importantly, translocation of the AKAP79/ 150 PKA complex from spines may shift the balance of PKA kinase and CaN/PP1 phosphatase activity at the postsynapse in favor of the phosphatases (Gomez et al., 2002). This loss of PKA could then promote actions of CaN and PP1 during induction of LTD (Lisman and Zhabotinsky, 2001; Morishita et al., 2001; Mulkey et al., 1994) including maintaining AMPAR dephosphorylation (Lee et al., 2000), promoting AMPAR endocytosis (Beattie et al., 2000), and preventing AMPAR recycling (Ehlers, 2000; Snyder et al., 2005) (Fig. 2C). Conclusions (1) AKAP79/150 is linked to both structural and signaling proteins in the PSD. (2) AKAP-anchored PKA and CaN are likely to regulate AMPAR phosphorylation and trafficking in LTD. (3) NMDAR regulation of AKAP79/150 postynaptic targeting during LTD is coordinated with changes in spine F-actin and CaN signaling. (4) Loss of AKAP79/150 and anchored PKA from synaptic MAGUK and cadherin complexes is coincident with CaN-mediated AMPAR dephosphorylation and removal from synapses during LTD. (5) Thus, loss of AKAP79/150 from synapse in response to NMDAR activation may promote changes in both synaptic structure and signaling that promote depression of AMPAR transmission. Overall, Our recent findings challenge the notion that AKAPs are static anchors and suggest that dynamic targeting regulation may allow AKAPs to function in novel ways to coordinate local changes in postsynaptic structure and signaling. References Ashby, M.C., De La Rue, S.A., Ralph, G.S., Uney, J., Collingridge, G.L., Henley, J.M., Removal of AMPA receptors (AMPARs) from synapses is preceded by transient endocytosis of extrasynaptic AMPARs. J. Neurosci. 24, Banke, T.G., Bowie, D., Lee, H., Huganir, R.L., Schousboe, A., Traynelis, S.F., Control of GluR1 AMPA receptor function by camp-dependent protein kinase. J. Neurosci. 20, Bauman, A.L., Goehring, A.S., Scott, J.D., Orchestration of synaptic plasticity through AKAP signaling complexes. Neuropharmacology 46, Beattie, E.C., Carroll, R.C., Yu, X., Morishita, W., Yasuda, H., von Zastrow, M., Malenka, R.C., Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD. Nat. Neurosci. 3, Blanpied, T.A., Scott, D.B., Ehlers, M.D., Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines. Neuron 36, Bozdagi, O., Shan, W., Tanaka, H., Benson, D.L., Huntley, G.W., Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to

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