NMDA receptor (NMDAR) associated proteins mini-review
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)
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 . AKAP79/150 regulates AMPA receptor phosphorylation and ion channel activity . 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) .
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 . In the brain Yotiao inhibits adenylyl cyclase (AC) 2 and 3, regulating cAMP production and acts as a scaffold for AC 1 and 9 . Yotiao binds to the NMDA receptor GluN1 (formerly NR1) subunit and is involved in the development of the brain and synaptic plasticity .
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 . Both AP-2 and clathrin are required for reformation of synaptic vesicles . 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 .
Postsynaptic density protein 93 (PSD93)
Postsynaptic density protein 93 (PSD93) is a MAGUK family scaffold protein also known as chapsyn-110 . 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 . 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 .
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