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Ionotropic Glutamate Receptors: Regulation by G-Protein-Coupled Receptors

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Ionotropic Glutamate Receptors: Regulation by G-Protein-Coupled Receptors 1521-0111/83/4/746–752$25.00 http://dx.doi.org/10.1124/mol.112.083352 MOLECULAR PHARMACOLOGY Mol Pharmacol 83:746–752, April 2013 Copyright ª 2013 by The American Society for Pharmacology and Experimental Therapeutics MINIREVIEW—SPECIAL ISSUE IN MEMORY OF AVRAM GOLDSTEIN Ionotropic Glutamate Receptors: Regulation by G-Protein-Coupled Receptors Asheebo Rojas and Raymond Dingledine Department of Pharmacology, Emory University, Atlanta, Georgia Received October 28, 2012; accepted January 23, 2013 Downloaded from ABSTRACT The function of many ion channels is under dynamic control by mitogen-activated–protein-kinase cascades. We focus here on the coincident activation of G-protein-coupled receptors (GPCRs), control of ionotropic glutamate receptor function by GPCR sig- particularly those coupled to the Gas and Gaq family members. naling because this form of regulation can influence the strength of molpharm.aspetjournals.org Such regulation is typically dependent on the subunit composition synaptic plasticity. The amino acid residues phosphorylated by of the ionotropic receptor or channel as well as the GPCR subtype specific kinases have been securely identified in many ionotropic and the cell-specific panoply of signaling pathways available. glutamate (iGlu) receptor subunits, but which of these sites are Because GPCRs and ion channels are so highly represented GPCR targets is less well known even when the kinase has been among targets of U.S. Food and Drug Administration-approved identified. N-methyl-D-aspartate, a-amino-3-hydroxy-5-methyl-4- drugs, functional cross-talk between these drug target classes isoxazolepropionic acid, and heteromeric kainate receptors are is likely to underlie many therapeutic and adverse effects of all downstream targets of GPCR signaling pathways. The details marketed drugs. GPCRs engage a myriad of signaling pathways of GPCR–iGlu receptor cross-talk should inform a better under- that involve protein kinases A and C (PKC) and, through PKC standing of how synaptic transmission is regulated and lead to and interaction with b-arrestin, Src kinase, and hence the new therapeutic strategies for neuropsychiatric disorders. at Emory University on March 26, 2013 Introduction the ability of mGlu1 to modulate voltage-dependent channels such as N-methyl-D-aspartate (NMDA) receptors will itself be Over 40% of U.S. Food and Drug Administration-approved voltage-dependent. The combination of phospho specific anti- drugs target either G-protein-coupled receptors (GCPR) or ion bodies, site-directed mutagenesis, and functional analysis has channels (Overington et al., 2006). Interestingly, these two allowed the secure identification of dynamically regulated classes of drug target often regulate one another by direct phosphorylation sites on many of the ionotropic glutamate physical interaction or through activation of signaling path- receptor subunits. However, convincing linkage of a specific ways. Signaling pathways underlying regulation take many G-protein-coupled receptor (GPCR) to one or more specific forms, including activation of Ser/Thr or tyrosine kinase cas- phosphorylated amino acids that regulate ionotropic re- cades by G-protein subunits or b-arrestin, with effector mech- ceptor function is uncommon. Several key questions re- anisms involving changes in protein-protein interactions main for control of glutamate receptor function by GPCRs: that anchor receptors to synaptic-scaffolding complexes and Which ionotropic glutamate (iGlu) receptors are regulated changes in channel gating or surface trafficking. Adding fur- by GPCRs, and in what cell types? Does the regulation ther nuance to this form of receptor cross-talk, the agonist occur directly (i.e., physical interaction of the GCPR with affinity for metabotropic glutamate receptor 1 (mGlu1) is regulatory/accessory and scaffolding proteins) or indirectly voltage-dependent due to a gating charge-driven conforma- via intracellular signaling molecules? If the latter, which tional change in the receptor (Ben-Chaim et al., 2006). Thus pathways are involved and which of the potential consensus phosphorylation sites on iGlu receptors are actually used? dx.doi.org/10.1124/mol.112.083352. How does cross-talk alter receptor and synaptic function? ABBREVIATIONS: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CaMKII, calcium/calmodulin-dependent protein kinase; GluA, AMPA receptor subunit; GluK, kainate receptor subunit; GluN, NMDA receptor subunit; GPCR, G-protein-coupled receptor; GRIP1, glutamate receptor interacting protein 1; iGlu, ionotropic glutamate; KARs, kainate receptors; LTD, long-term depression; LTP, long-term potentiation; mACh, muscarinic acetylcholine; mGlu, metabotropic glutamate receptor; MOR, mu opioid receptors; NMDA, N-methyl-D-aspartate; NMDAR, NMDA receptor; PACAP, pituitary adenylate cyclase-activating peptide; PDZ, postsynaptic density 95/disc-large/ZO-1; PICK1, protein interacting with C kinase 1; PKA, protein kinase A; PKC, protein kinase C; PSD, postsynaptic density; Pyk2/PYK2, proline-rich tyrosine kinase 2; RACK1, receptor for activated C kinase 1. 746 GPCR–iGlu Receptor Cross-Talk 747 Here we review the regulation of ionotropic glutamate recep- Regulation of NMDARs by mGlu and mACh Recep- tors [a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid tors. Metabotropic glutamate receptors modulate neuronal ex- (AMPA), NMDA, and kainate] by GPCRs with special at- citability via regulation of voltage-sensitive calcium channels, 1 tentiononGaq-coupled mGlu and muscarinic acetylcholine G-protein-regulated inward rectifier K channels, GABAA re- (mACh) receptor, as these GPCRs are critically involved ceptors, AMPA receptors, and NMDA receptors (Conn and Pin, in synaptic transmission and plasticity and their altered 1997). Eight mGlu receptors are classified into three groups regulation has significant implications in neuropathies. according to their Ga protein. Group I mGlu receptors (mGlu1 and mGlu5) are coupled to Gaq family members and activate Ionotropic Glutamate Receptors the phospholipase C pathway, which leads to an increase in diacylglycerol and inositol trisphosphate levels, intracellular Ionotropic glutamate receptors are classified functionally and calcium, and stimulation of PKC (Fig. 1A). An important by molecular homology into three receptor classes: NMDA consequence of group I mGlu activation is modulation of (consisting of the GluN1, GluN2A, GluN2B, GluN2C, GluN2D, glutamatergic transmission, for example, potentiated NMDAR GluN3A, and GluN3B subunits), AMPA (GluA1, GluA2, GluA3, responses in the hippocampus, cerebellum, cortex, and spinal and GluA4), and kainate (GluK1, GluK2, GluK3, GluK4, and cord (Bordi and Ugolini, 1999). Activation of group I mGlu GluK5). Ionotropic glutamate receptors are tetrameric assem- receptors in striatal neurons increases GluN1 phosphorylation blies of multiple subunits. Subunit assembly appears exclusive at serines 896 and 897 in vivo. The GluN1 phosphorylation was Downloaded from within a receptor class; for example, none of the four AMPA attenuated in the presence of an mGlu5 antagonist suggesting receptor subunits has been shown to coassemble with NMDA that the phosphorylation is mGlu5-mediated (Choe et al., 2006). receptor subunits to form a functional receptor. We will consider The kinase(s) responsible for the phosphorylation was not iden- cross-talk regulation of each ionotropic receptor class in turn. tified in this study. However, functional cross-talk was observed in human embryonic kidney 293 cells expressing NMDARs containing the GluN2A and GluN2B subunits as well as the NMDA Receptor Modulation molpharm.aspetjournals.org mGlu1 receptor, where activation of mGlu1 resulted in in- The regulation of NMDA receptor (NMDAR) currents can creased phosphorylation of GluN2A and GluN2B by a Src occur through phosphorylation of regulatory sites located family tyrosine kinase (Heidinger et al., 2002), suggestive of a within the GluN1 or GluN2 subunits or via protein-protein b-arrestin or PKC-pathway involvement. Although mGlu1 and interactions, in which changes in the binding of proteins like mGlu5 are both coupled to Gaq and they both can potentiate postsynaptic density (PSD)-95 or calmodulin help to cluster NMDA receptor currents in CA3 pyramidal cells, they appear NMDARs at postsynaptic sites. The distal C terminus of GluN2 to do so via two distinct signaling pathways, mGlu1 via a subunits contains postsynaptic density 95/disc-large/ZO-1 G-protein-independent Src kinase pathway possibly involving (PDZ) motifs that noncovalently link NMDA receptors to scaf- b-arrestin, and mGlu5 via a Gaq-PKC-PYK2 (proline-rich at Emory University on March 26, 2013 folding proteins like those in the PSD-95 family and its asso- tyrosine kinase 2)-Src pathway (Benquet et al., 2002). ciated proteins—membrane-associated guanylate kinase and Neuronal excitability and synaptic transmission are also A-kinase anchoring protein. All four GluN2 subunits appear to altered by interactions between the cholinergic and gluta- interact with all four PSD-95 proteins (PSD-95, PSD-93, matergic neurotransmitter systems. One mechanism involves SAP102, SAP97) typically resulting in a change in surface potentiation of NMDA receptor currents by M1 muscarinic targeting of NMDA receptors (Bard and Groc, 2011). Over the receptors, which colocalize with the GluN1 subunit in hip- past two decades attention has also focused on the indirect pocampal CA1 pyramidal cells (Marino et al., 1998). Poten- regulation of NMDARs mediated
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