NMDA receptor (NMDAR) associated proteins mini-review

NMDA associated proteins mini-reviewOverview

 There are many proteins (auxillary subunits and interacting proteins) that are associated with glutamate receptors and that have important roles in the transport receptors and structural roles tethering other proteins.

Auxilliary subunits are not an integral component of the transduction pathway. They are stably associated with their partner receptor and affect multiple aspects of receptor pharmacology, function, and subcellular trafficking or targeting. Co-assembly is required for proper neuronal functionality of the receptor

Interacting proteins have transient and often dynamic interactions with receptors and influence singular aspects of receptor function (e.g. biogenesis, trafficking or synaptic localization).

Some of the major NMDA receptor interacting proteins are described below.

A Kinase Anchoring Proteins (AKAPs)

NMDA receptor structure showing binding sites

A kinase-anchoring proteins (AKAPS) are required for protein kinase A (PKA) activity at the synapse. NMDA displaces PKA and inhibits its function at the synapse, disrupting the AKAP-PKA interaction causes a loss of AMPA receptors from the synapse [1]. AKAP79/150 regulates AMPA receptor phosphorylation and ion channel activity [2]. The AKAP150-PSD95 complex binds to GluA1 subunit and mediates synaptic plasticity by interacting with PKA and calcineurin during long-term depression (LTD) and potentiation (LTP) [3].

Yotiao (also known as AKAP9) is a protein kinase A (PKA) anchoring protein found in the neuromuscular junction and the brain [4, 5]. In the heart Yotiao acts with PKA to regulate the slow outward potassium ion current [4]. In the brain Yotiao inhibits adenylyl cyclase (AC) 2 and 3, regulating cAMP production and acts as a scaffold for AC 1 and 9 [6]. Yotiao binds to the NMDA receptor GluN1 (formerly NR1) subunit and is involved in the development of the brain and synaptic plasticity [7].

Adaptor protein-2 (AP-2)

AP-2 Adaptor protein-2 (AP-2) is a heterotetramer that regulates receptor-mediated endocytosis at the plasma membrane, recruiting clathrin to form clathrin-coated vesicles [8]. Both AP-2 and clathrin are required for reformation of synaptic vesicles [9]. AP-2 internalisation of AMPA receptors is induced by NMDA receptors for LTD in the hippocampus. The protein binds to AMPA receptors at the GluA2 subunit overlapping with the NSF binding site [10, 11]. AP-2 also binds to NMDA receptor GluN2B subunits to mediate internalization of the receptor [12, 13].

Postsynaptic density protein 95 (PSD95)

Postsynaptic density protein 95 (PSD95) is a membrane-associated guanylate kinase (MAGUK) family scaffold protein. The PDZ domain of PSD95 binds to the C terminus domains of GluN2A, GluN2B and GluN2C to anchor NMDA receptors to the membrane cytoskeleton [14, 15]. PSD95 is involved in NMDA receptor long-term potentiation and synaptic maturation in the superior colliculus; decreasing expression of PSD95 is associated with cognitive impairment [16, 17]. Levels of PSD95 are decreased in association with neurodegenerative diseases such as Alzheimer’s disease [17].

Postsynaptic density protein 93 (PSD93)

Postsynaptic density protein 93 (PSD93) is a MAGUK family scaffold protein also known as chapsyn-110 [18]. It stabilises neuronal cholinergic synapses by forming a complex with nACh receptors and interacts with GluD2 receptors [19, 20]. PSD93 binds to NMDA receptors and Shaker K+ channels forming clusters at the postsynaptic membrane [18, 21]. The protein is associated with memory and synaptic plasticity [22, 23].

Synapse-associated protein 102 (SAP102)

Synapse-associated protein 102 (SAP102) is a MAGUK family protein that binds to many other proteins [24]. SAP102 regulates EphB and PAK signaling pathways and is involved in AMPA receptor trafficking. It also binds with NMDA receptors for trafficking to the synaptic membrane and clearance of GluN2B subunit-containing NMDA receptors from the synapse [24, 25, 26]. High levels of SAP102 are expressed during cognitive development [27, 28].

Shank is a postsynaptic density scaffold protein in glutamatergic synapses with a similar distribution to Homer. The protein accumulates after stimulation with NMDA and NMDA receptor activation, mediated by CaMKII [29, 30]. Shank proteins interact with NMDA and metabotropic receptors at the postsynaptic membrane; the proteins recruit β-PIX and PAK and organise multiprotein complexes [31, 32, 33]. Mutated SHANK genes have been linked to autism and cognitive dysfunction with dysfunctional long term potentiation [34].


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2, Keith DJ et al., 2012 Palmitoylation of A-kinase anchoring protein 79/150 regulates dendritic endosomal targeting and synaptic plasticity mechanisms. J Neurosci 32(21):7119-36 Pubmed ID: 22623657

3, Sanderson JL, Gorski JA, Gibson ES, Lam P, Freund RK, Chick WS, Dell'Acqua ML 2012 AKAP150-anchored calcineurin regulates synaptic plasticity by limiting synaptic incorporation of Ca2+-permeable AMPA receptors. J Neurosci 32(43):15036-52 Pubmed ID: 23100425

4, Chen L, Kass RS 2006 Dual roles of the A kinase-anchoring protein Yotiao in the modulation of a cardiac potassium channel: a passive adaptor versus an active regulator. Eur J Cell Biol 85(7):623-6 Pubmed ID: 16647783

5, Lin JW et al., 1998 Yotiao, a novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1. J Neurosci 18(6):2017-27 Pubmed ID: 9482789

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7, Feliciello A, Cardone et al., 1999 Yotiao protein, a ligand for the NMDA receptor, binds and targets cAMP-dependent protein kinase II(1). FEBS Lett 464(3):174-8 Pubmed ID: 10618500

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9, Kononenko NL et al., 2014 Clathrin/AP-2 mediate synaptic vesicle reformation from endosome-like vacuoles but are not essential for membrane retrieval at central synapses. Neuron 82(5):981-8 Pubmed ID: 24908483

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14, Niethammer M, Kim E, Sheng M 1996 Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases. J Neurosci 16(7):2157-63 Pubmed ID: 8601796

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16, Zhao JP, Murata Y, Constantine-Paton M 2013 Eye opening and PSD95 are required for long-term potentiation in developing superior colliculus. Proc Natl Acad Sci U S A 110(2):707-12 Pubmed ID: 23267080

17, Whitfield DR et al., 2014 Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: association with cognitive impairment. Neurobiol Aging 35(12):2836-44 Pubmed ID: 25104558

18, Kim E, Cho KO, Rothschild A, Sheng M 1996 Heteromultimerization and NMDA receptor-clustering activity of Chapsyn-110, a member of the PSD-95 family of proteins. Neuron 17(1):103-13 Pubmed ID: 8755482

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23, Zhu LQ, Wang SH, Liu D, Yin YY, Tian Q, Wang XC, Wang Q, Chen JG, Wang JZ 2007 Activation of glycogen synthase kinase-3 inhibits long-term potentiation with synapse-associated impairments. J Neurosci 27(45):12211-20 Pubmed ID: 17989287

24, Minatohara K, Ichikawa SH, Seki T, Fujiyoshi Y, Doi T 2013 Ligand binding of PDZ domains has various roles in the synaptic clustering of SAP102 and PSD-95. Neurosci Lett 533:44-9 Pubmed ID: 23178474

25, Lim IA, Hall DD, Hell JW 2002 Selectivity and promiscuity of the first and second PDZ domains of PSD-95 and synapse-associated protein 102. J Biol Chem 277(24):21697-711 Pubmed ID: 11937501

26, Chen BS, Gray JA, Sanz-Clemente A, Wei Z, Thomas EV, Nicoll RA, Roche KW 2012 SAP102 mediates synaptic clearance of NMDA receptors. Cell Rep 2(5):1120-8 Pubmed ID: 23103165

27, Murata Y, Constantine-Paton M 2013 Postsynaptic density scaffold SAP102 regulates cortical synapse development through EphB and PAK signaling pathway. J Neurosci 33(11):5040-52 Pubmed ID: 23486974

28, Sans N et al., 2000 A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J Neurosci 20(3):1260-71 Pubmed ID: 10648730

29, Tao-Cheng JH, Thein S, Yang Y, Reese TS, Gallant PE 2014 Homer is concentrated at the postsynaptic density and does not redistribute after acute synaptic stimulation. Neuroscience 266:80-90 Pubmed ID: 24530450

30, Tao-Cheng JH, Yang Y, Bayer KU, Reese TS, Dosemeci A 2014 NMDA-induced accumulation of Shank at the postsynaptic density is mediated by CaMKII. Biochem Biophys Res Commun 450(1):808-11 Pubmed ID: 24952157

31, Park E, Na M, Choi J, Kim S, Lee JR, Yoon J, Park D, Sheng M, Kim E 2003 The Shank family of postsynaptic density proteins interacts with and promotes synaptic accumulation of the beta PIX guanine nucleotide exchange factor for Rac1 and Cdc42. J Biol Chem 278(21):19220-9 Pubmed ID: 12626503

32, Boeckers TM, Bockmann J, Kreutz MR, Gundelfinger ED 2002 ProSAP/Shank proteins - a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease. J Neurochem 81(5):903-10 Pubmed ID: 12065602

33, Sheng M, Kim E 2000 The Shank family of scaffold proteins. J Cell Sci 113 ( Pt 11):1851-6 Pubmed ID: 10806096

34, Leblond CS et al., 2014 Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. PLoS Genet 10(9):e1004580 Pubmed ID: 25188300