mGlu receptor (mGluR) associated proteins mini-review

Overview

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.

GRIP

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 [4]. GRIP is down-regulated in response to glutamate stimulation [2]. 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 [1].

Homer

Homer proteins are postsynaptic density scaffold proteins that have many functions. Homer proteins mediate glutamate receptor signal transduction [7]. 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 [8].

Shank

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 [16].

PICK1

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 [21].

SAP102

Synapse-associated protein 102 (SAP102) is a membrane-associated guanylate kinase (MAGUK) family protein that binds to many other proteins [22]. 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].

References

1, Takamiya K, Mao L, Huganir RL, Linden DJ 2008. The glutamate receptor-interacting protein family of GluR2-binding proteins is required for long-term synaptic depression expression in cerebellar Purkinje cells. J Neurosci. 28(22):5752-5. Pubmed ID: 18509036

2, Guo L, Wang Y 2007. Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. Neuroscience. 145(1):100-9. Pubmed ID: 17207582

3, Hirbec H, Francis JC, Lauri SE, Braithwaite SP, Coussen F, Mulle C, Dev KK, Coutinho V, Meyer G, Isaac JT, Collingridge GL, Henley JM 2003. Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP. Neuron. 37(4):625-38. Pubmed ID: 12597860

4, Kulangara K, Kropf M, Glauser L, Magnin S, Alberi S, Yersin A, Hirling H 2007. Phosphorylation of glutamate receptor interacting protein 1 regulates surface expression of glutamate receptors. J Biol Chem. 282(4):2395-404. Pubmed ID: 17121843

5, Davidkova G, Carroll RC 2007. Characterization of the role of microtubule-associated protein 1B in metabotropic glutamate receptor-mediated endocytosis of AMPA receptors in hippocampus. J Neurosci. 27(48):13273-8. Pubmed ID: 18045921

6, Gladding CM, Fitzjohn SM, Molnar E 2009. Metabotropic glutamate receptor-mediated long-term depression: molecular mechanisms. Pharmacol Rev. 61(4):395-412. Pubmed ID: 19926678

7, Luo P, Chen T, Zhao Y, Zhang L, Yang Y, Liu W, Li S, Rao W, Dai S, Yang J, Fei Z 2014. Postsynaptic scaffold protein Homer 1a protects against traumatic brain injury via regulating group I metabotropic glutamate receptors. Cell Death Dis. 5:e1174. Pubmed ID: 24722299

8, 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

9, Tu JC, Xiao B, Yuan JP, Lanahan AA, Leoffert K, Li M, Linden DJ, Worley PF 1998. Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors. Neuron. 21(4):717-26. Pubmed ID: 9808459

10, Shiraishi-Yamaguchi Y, Furuichi T 2007. The Homer family proteins. Genome Biol. 8(2):206. Pubmed ID: 17316461

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

12, 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

13, 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

14, 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

15, 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

16, 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

17, Pinheiro PS, Jansen AM, de Wit H, Tawfik B, Madsen KL, Verhage M, Gether U, Sorensen JB 2014. The BAR domain protein PICK1 controls vesicle number and size in adrenal chromaffin cells. J Neurosci. 34(32):10688-700. Pubmed ID: 25100601

18, Erlendsson S, Rathje M, Heidarsson PO, Poulsen FM, Madsen KL, Teilum K, Gether U 2014. Protein interacting with C-kinase 1 (PICK1) binding promiscuity relies on unconventional PSD-95/discs-large/ZO-1 homology (PDZ) binding modes for nonclass II PDZ ligands. J Biol Chem. 289(36):25327-40. Pubmed ID: 25023278

19, Hirbec H, Francis JC, Lauri SE, Braithwaite SP, Coussen F, Mulle C, Dev KK, Coutinho V, Meyer G, Isaac JT, Collingridge GL, Henley JM 2003. Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP. Neuron. 37(4):625-38. Pubmed ID: 12597860

20, Dev KK, Nakajima Y, Kitano J, Braithwaite SP, Henley JM, Nakanishi S 2000. PICK1 interacts with and regulates PKC phosphorylation of mGLUR7. J Neurosci. 20(19):7252-7. Pubmed ID: 11007882

21, Wang Z, Wang YN, Sun CL, Yang D, Su LD, Xie YJ, Zhou L, Wang Y, Shen Y 2013. C-terminal domain of ICA69 interacts with PICK1 and acts on trafficking of PICK1-PKCÎ± complex and cerebellar plasticity. PLoS One. 8(12):e83862. Pubmed ID: 24358315

22, 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

23, 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

24, 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

25, 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

26, Sans N, Petralia RS, Wang YX, Blahos J 2nd, Hell JW, Wenthold RJ 2000. A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J Neurosci. 20(3):1260-71. Pubmed ID: 10648730