Preso1 dynamically regulates group I metabotropic glutamate receptors

Abstract

Group I metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, are G protein–coupled receptors (GPCRs) that are expressed at excitatory synapses in brain and spinal cord. GPCRs are often negatively regulated by specific G protein–coupled receptor kinases and subsequent binding of arrestin-like molecules. Here we demonstrate an alternative mechanism in which group I mGluRs are negatively regulated by proline-directed kinases that phosphorylate the binding site for the adaptor protein Homer, and thereby enhance mGluR–Homer binding to reduce signaling. This mechanism is dependent on a multidomain scaffolding protein, Preso1, that binds mGluR, Homer and proline-directed kinases and that is required for their phosphorylation of mGluR at the Homer binding site. Genetic ablation of Preso1 prevents dynamic phosphorylation of mGluR5, and Preso1−/− mice exhibit sustained, mGluR5-dependent inflammatory pain that is linked to enhanced mGluR signaling. Preso1 creates a microdomain for proline-directed kinases with broad substrate specificity to phosphorylate mGluR and to mediate negative regulation.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Preso1 binds to Homer and localizes to the postsynaptic density.
Figure 2: Preso1 binds to the mGluR5 C terminus by means of its FERM domain.
Figure 3: Preso1 enhances mGluR5 phosphorylation and Homer–mGluR5 binding, and inhibits group I mGluR coupling to voltage-gated Ca2+ channels.
Figure 4: Preso1 binds proline-directed kinases and enhances kinase-mGluR5 binding.
Figure 5: Preso1 is required for activity-dependent increase of mGluR5 phosphorylation and Homer binding.
Figure 6: Increased pain response to formalin or complete Freund's adjuvant in Preso1−/− mice.
Figure 7: Enhanced group I mGluR-mediated calcium response in the spinal cord neurons of Preso1−/− mice.

References

  1. 1

    Lüscher, C. & Huber, K.M. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65, 445–459 (2010).

    Article  Google Scholar 

  2. 2

    Chiamulera, C. et al. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat. Neurosci. 4, 873–874 (2001).

    CAS  Article  Google Scholar 

  3. 3

    Bhave, G., Karim, F., Carlton, S.M. & Gereau, R.W.t. Peripheral group I metabotropic glutamate receptors modulate nociception in mice. Nat. Neurosci. 4, 417–423 (2001).

    CAS  Article  Google Scholar 

  4. 4

    Niswender, C.M. & Conn, P.J. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu. Rev. Pharmacol. Toxicol. 50, 295–322 (2010).

    CAS  Article  Google Scholar 

  5. 5

    Lujan, R., Nusser, Z., Roberts, J.D., Shigemoto, R. & Somogyi, P. Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus. Eur. J. Neurosci. 8, 1488–1500 (1996).

    CAS  Article  Google Scholar 

  6. 6

    Torres, G.E. & Amara, S.G. Glutamate and monoamine transporters: new visions of form and function. Curr. Opin. Neurobiol. 17, 304–312 (2007).

    CAS  Article  Google Scholar 

  7. 7

    Kammermeier, P.J., Xiao, B., Tu, J.C., Worley, P.F. & Ikeda, S.R. Homer proteins regulate coupling of group I metabotropic glutamate receptors to N-type calcium and M-type potassium channels. J. Neurosci. 20, 7238–7245 (2000).

    CAS  Article  Google Scholar 

  8. 8

    Tu, J.C. et al. Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors. Neuron 21, 717–726 (1998).

    CAS  Article  Google Scholar 

  9. 9

    Park, S. et al. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron 59, 70–83 (2008).

    CAS  Article  Google Scholar 

  10. 10

    Wang, J.Q., Fibuch, E.E. & Mao, L. Regulation of mitogen-activated protein kinases by glutamate receptors. J. Neurochem. 100, 1–11 (2007).

    CAS  Article  Google Scholar 

  11. 11

    Hou, L. & Klann, E. Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J. Neurosci. 24, 6352–6361 (2004).

    CAS  Article  Google Scholar 

  12. 12

    Galante, M. & Diana, M.A. Group I metabotropic glutamate receptors inhibit GABA release at interneuron-Purkinje cell synapses through endocannabinoid production. J. Neurosci. 24, 4865–4874 (2004).

    CAS  Article  Google Scholar 

  13. 13

    Brakeman, P.R. et al. Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 386, 284–288 (1997).

    CAS  Article  Google Scholar 

  14. 14

    Ango, F. et al. Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer. Nature 411, 962–965 (2001).

    CAS  Article  Google Scholar 

  15. 15

    Dhavan, R. & Tsai, L.H. A decade of CDK5. Nat. Rev. Mol. Cell Biol. 2, 749–759 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Lee, H.W. et al. Preso, a novel PSD-95-interacting FERM and PDZ domain protein that regulates dendritic spine morphogenesis. J. Neurosci. 28, 14546–14556 (2008).

    CAS  Article  Google Scholar 

  17. 17

    Zhong, H. et al. Subcellular dynamics of type II PKA in neurons. Neuron 62, 363–374 (2009).

    CAS  Article  Google Scholar 

  18. 18

    An, N., Blumer, J.B., Bernard, M.L. & Lanier, S.M. The PDZ and band 4.1 containing protein Frmpd1 regulates the subcellular location of activator of G-protein signaling 3 and its interaction with G-proteins. J. Biol. Chem. 283, 24718–24728 (2008).

    CAS  Article  Google Scholar 

  19. 19

    Xiao, B. et al. Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins. Neuron 21, 707–716 (1998).

    CAS  Article  Google Scholar 

  20. 20

    Hoover, K.B. & Bryant, P.J. The genetics of the protein 4.1 family: organizers of the membrane and cytoskeleton. Curr. Opin. Cell Biol. 12, 229–234 (2000).

    CAS  Article  Google Scholar 

  21. 21

    Sharrocks, A.D., Yang, S.H. & Galanis, A. Docking domains and substrate-specificity determination for MAP kinases. Trends Biochem. Sci. 25, 448–453 (2000).

    CAS  Article  Google Scholar 

  22. 22

    Huang, G.N. et al. NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. Science 319, 476–481 (2008).

    CAS  Article  Google Scholar 

  23. 23

    Orlando, L.R. et al. Phosphorylation of the homer-binding domain of group I metabotropic glutamate receptors by cyclin-dependent kinase 5. J. Neurochem. 110, 557–569 (2009).

    CAS  Article  Google Scholar 

  24. 24

    Kammermeier, P.J. & Ikeda, S.R. Expression of RGS2 alters the coupling of metabotropic glutamate receptor 1a to M-type K+ and N-type Ca2+ channels. Neuron 22, 819–829 (1999).

    CAS  Article  Google Scholar 

  25. 25

    Gallagher, S.M., Daly, C.A., Bear, M.F. & Huber, K.M. Extracellular signal-regulated protein kinase activation is required for metabotropic glutamate receptor-dependent long-term depression in hippocampal area CA1. J. Neurosci. 24, 4859–4864 (2004).

    CAS  Article  Google Scholar 

  26. 26

    Segal, R.A. & Greenberg, M.E. Intracellular signaling pathways activated by neurotrophic factors. Annu. Rev. Neurosci. 19, 463–489 (1996).

    CAS  Article  Google Scholar 

  27. 27

    Kitano, J. et al. Tamalin, a PDZ domain-containing protein, links a protein complex formation of group 1 metabotropic glutamate receptors and the guanine nucleotide exchange factor cytohesins. J. Neurosci. 22, 1280–1289 (2002).

    CAS  Article  Google Scholar 

  28. 28

    Ferreira, L.T. et al. Calcineurin inhibitor protein (CAIN) attenuates Group I metabotropic glutamate receptor endocytosis and signaling. J. Biol. Chem. 284, 28986–28994 (2009).

    CAS  Article  Google Scholar 

  29. 29

    Wang, H. et al. Norbin is an endogenous regulator of metabotropic glutamate receptor 5 signaling. Science 326, 1554–1557 (2009).

    CAS  Article  Google Scholar 

  30. 30

    Hu, J.H. et al. Homeostatic scaling requires group I mGluR activation mediated by Homer1a. Neuron 68, 1128–1142 (2010).

    CAS  Article  Google Scholar 

  31. 31

    Hunskaar, S. & Hole, K. The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 30, 103–114 (1987).

    CAS  Article  Google Scholar 

  32. 32

    Puig, S. & Sorkin, L.S. Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity. Pain 64, 345–355 (1996).

    CAS  Article  Google Scholar 

  33. 33

    Cozzoli, D.K. et al. Binge drinking upregulates accumbens mGluR5-Homer2–PI3K signaling: functional implications for alcoholism. J. Neurosci. 29, 8655–8668 (2009).

    CAS  Article  Google Scholar 

  34. 34

    Sheng, M., McFadden, G. & Greenberg, M.E. Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB. Neuron 4, 571–582 (1990).

    CAS  Article  Google Scholar 

  35. 35

    Alvarez, F.J., Villalba, R.M., Carr, P.A., Grandes, P. & Somohano, P.M. Differential distribution of metabotropic glutamate receptors 1a, 1b, and 5 in the rat spinal cord. J. Comp. Neurol. 422, 464–487 (2000).

    CAS  Article  Google Scholar 

  36. 36

    Kim, S.J. et al. Transient upregulation of postsynaptic IP3-gated Ca release underlies short-term potentiation of metabotropic glutamate receptor 1 signaling in cerebellar Purkinje cells. J. Neurosci. 28, 4350–4355 (2008).

    CAS  Article  Google Scholar 

  37. 37

    Gainetdinov, R.R., Premont, R.T., Bohn, L.M., Lefkowitz, R.J. & Caron, M.G. Desensitization of G protein-coupled receptors and neuronal functions. Annu. Rev. Neurosci. 27, 107–144 (2004).

    CAS  Article  Google Scholar 

  38. 38

    Dhami, G.K. & Ferguson, S.S. Regulation of metabotropic glutamate receptor signaling, desensitization and endocytosis. Pharmacol. Ther. 111, 260–271 (2006).

    CAS  Article  Google Scholar 

  39. 39

    Bernier, S.G., Haldar, S. & Michel, T. Bradykinin-regulated interactions of the mitogen-activated protein kinase pathway with the endothelial nitric-oxide synthase. J. Biol. Chem. 275, 30707–30715 (2000).

    CAS  Article  Google Scholar 

  40. 40

    Hu, H.J., Alter, B.J., Carrasquillo, Y., Qiu, C.S. & Gereau, R.W. Metabotropic glutamate receptor 5 modulates nociceptive plasticity via extracellular signal-regulated kinase-Kv4.2 signaling in spinal cord dorsal horn neurons. J. Neurosci. 27, 13181–13191 (2007).

    CAS  Article  Google Scholar 

  41. 41

    Utreras, E., Futatsugi, A., Pareek, T.K. & Kulkarni, A.B. Molecular Roles of Cdk5 in Pain Signaling. Drug Discov. Today Ther. Strateg. 6, 105–111 (2009).

    CAS  Article  Google Scholar 

  42. 42

    Tronson, N.C. et al. Metabotropic glutamate receptor 5/Homer interactions underlie stress effects on fear. Biol. Psychiatry 68, 1007–1015 (2010).

    CAS  Article  Google Scholar 

  43. 43

    Latremoliere, A. & Woolf, C.J. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J. Pain 10, 895–926 (2009).

    Article  Google Scholar 

  44. 44

    Neugebauer, V., Li, W., Bird, G.C., Bhave, G. & Gereau, R.W.t. Synaptic plasticity in the amygdala in a model of arthritic pain: differential roles of metabotropic glutamate receptors 1 and 5. J. Neurosci. 23, 52–63 (2003).

    CAS  Article  Google Scholar 

  45. 45

    Bear, M.F. Therapeutic implications of the mGluR theory of fragile X mental retardation. Genes Brain Behav. 4, 393–398 (2005).

    CAS  Article  Google Scholar 

  46. 46

    Rocher, J.P. et al. mGluR5 negative allosteric modulators overview: a medicinal chemistry approach towards a series of novel therapeutic agents. Curr. Top. Med. Chem. 11, 680–695 (2011).

    CAS  Article  Google Scholar 

  47. 47

    Yuan, J.P. et al. Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors. Cell 114, 777–789 (2003).

    CAS  Article  Google Scholar 

  48. 48

    Choi, K.Y., Satterberg, B., Lyons, D.M. & Elion, E.A. Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae. Cell 78, 499–512 (1994).

    CAS  Article  Google Scholar 

  49. 49

    Wong, W. & Scott, J.D. AKAP signalling complexes: focal points in space and time. Nat. Rev. Mol. Cell Biol. 5, 959–970 (2004).

    CAS  Article  Google Scholar 

  50. 50

    Lu, Y.M. et al. Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J. Neurosci. 17, 5196–5205 (1997).

    CAS  Article  Google Scholar 

  51. 51

    Petralia, R.S. et al. Selective acquisition of AMPA receptors over postnatal development suggests a molecular basis for silent synapses. Nat. Neurosci. 2, 31–36 (1999).

    CAS  Article  Google Scholar 

  52. 52

    Kim, A.Y. et al. Pirt, a phosphoinositide-binding protein, functions as a regulatory subunit of TRPV1. Cell 133, 475–485 (2008).

    CAS  Article  Google Scholar 

  53. 53

    Liu, Q. et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139, 1353–1365 (2009).

    Article  Google Scholar 

Download references

Acknowledgements

We thank J. Roder of University of Toronto for Grm5−/− mice, J. Worley for help with behavioral experiments and Y.-X. Wang for help with the immunogold. This work was supported by US National Institutes of Health grants from the National Institute on Drug Abuse (DA010309), National Institute of Mental Health (MH084020) and National Institute of Neurological Disorders and Stroke (NS050274 (P.F.W.); NS054791 and GM087369 (X.D.)); National 973 Basic Research Program of China (20009CB941400; B.X.); and the National Institute on Deafness and Other Communication Disorders Intramural Research Program (R.S.P.).

Author information

Affiliations

Authors

Contributions

J.-H.H. designed, performed and analyzed experiments included in Figures 1, 2, 3, 4, 5, 6, 7 and Supplementary Figures 1–6 and 8, and wrote a first draft of the manuscript. L.Y. performed and analyzed experiments in Figures 1 and 2 and Supplementary Figure 4. P.J.K. performed and analyzed electrophysiology experiments in Figure 3. C.G.M. generated and identified the phospho-mGluR antibody in Supplementary Figure 4. P.R.B. performed the yeast-two hybrid screen that identified Preso1 as a Homer binding protein. J.T. and B.X. cloned Preso1 and did initial characterizations. S.Y. generated the Preso1 antibody. R.S.P. performed the experiments in Figure 1. Z.L. performed and analyzed experiments in Supplementary Figure 7. P.-W.Z. generated Grm5R/R mice. J.M.P. performed electrophysiological experiments. X.D. provided intellectual input and technical support on the behavioral experiments and dorsal root ganglion neuron recordings. B.X. generated Preso1 antibodies, designed and performed experiments in Figure 1 and provided intellectual input and technical support for Preso1−/− mouse generation. P.F.W. supervised the overall project, designed experiments and wrote the final version of the manuscript.

Corresponding author

Correspondence to Paul F Worley.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–13 (PDF 5219 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hu, JH., Yang, L., Kammermeier, P. et al. Preso1 dynamically regulates group I metabotropic glutamate receptors. Nat Neurosci 15, 836–844 (2012). https://doi.org/10.1038/nn.3103

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing