mGlu receptor (mGluR) associated proteins mini-review
There are many proteins associated with metabotropic glutamate receptors with important roles in transport of the receptor and structural roles tethering other proteins. Some of the major associated proteins are described here.
Glutamate receptor-interacting proteins, GRIP1 and GRIP2, couple AMPA receptors containing the GluA2 subunit to signalling complexes with GluA2 binding at the PDZ5 domain of the GRIP proteins [1, 2, 3]. GRIP regulates the expression of AMPA receptors at the synapse and therefore the strength of excitation . GRIP is down-regulated in response to glutamate stimulation . Metabotropic glutamate receptors upregulate MAP1B expression, increasing MAP1B-GRIP interactions and promoting AMPA receptor endocytosis [5, 6]. GRIP proteins are required for cerebellar long-term depression .
Homer proteins are postsynaptic density scaffold proteins that have many functions. Homer proteins mediate glutamate receptor signal transduction . The proteins act with Shank proteins to link mGlu receptors to inositol trisphosphate receptors (IP3R) triggering calcium release and signaling pathways [8, 9, 10, 11]. Homer 1 is a protein found in the central nervous system and in peripheral tissues that cross links proteins while Homer 2 and 3 proteins are found in dendrites [9, 10]. Homer proteins are involved in synaptic plasticity .
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 [12, 13]. Shank proteins interact with NMDA and metabotropic receptors at the postsynaptic membrane; the proteins recruit β-PIX and PAK and organise multiprotein complexes [11, 14, 15]. Mutated SHANK genes have been linked to autism and cognitive dysfunction with dysfunctional long term potentiation .
Protein Interacting with C Kinase 1 (PICK1) is a BAR (Bin–Amphiphysin–Rvs) domain protein that interacts with transporters, receptors and kinases through a PDZ domain [17, 18]. It stabilises kainate receptors at the cell surface, regulates mGlu7 phosphorylation and influences the biogenesis of vesicles for AMPA receptor trafficking [19, 20]. PICK-1 is required for synaptic plasticity; it forms a complex with PKC-α inducing GluA2 internalisation for the induction of long-term depression .
Synapse-associated protein 102 (SAP102) is a membrane-associated guanylate kinase (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 [22, 23, 24]. High levels of SAP102 are expressed during cognitive development [25, 26].
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