Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

PDZ domain proteins of synapses

Nature Reviews Neuroscience volume 5, pages 771–781 (2004)Cite this article

Key Points

  • PDZ domains are modular protein-interaction domains that are specialized for binding to C-terminal peptide motifs of other proteins. PDZ-domain-based scaffolds typically assemble large molecular complexes at specific subcellular sites, such as synapses.

  • The postsynaptic density (PSD) of brain excitatory synapses contains many PDZ proteins, of which PSD-95 is the best characterized.

  • PSD-95 contains multiple domains that mediate its association with various membrane proteins (receptors, ion channels and cell-adhesion molecules) and cytoplasmic signalling molecules. PSD-95 influences the activity of interacting membrane proteins by controlling their surface delivery, stability, subcellular location, subunit composition and even intrinsic functional properties. By linking them with cytoplasmic signal transduction proteins, PSD-95 facilitates the functional coupling of postsynaptic receptors and ion channels to downstream signalling pathways involving nitric oxide, Ras, Rap and Rac.

  • Molecular genetic manipulations of PSD-95 in culture and in vivo have strong effects on synaptic transmission and plasticity. The abundance and activity of PSD-95 at synapses is dynamically controlled by activity, palmitoylation (lipid modification), degradation and phosphorylation.

  • The four members of the PSD-95 family of proteins show distinct patterns of palmitoylation, subcellular localization, temporal expression and binding partners, which presumably underlie their differential functions in synapses and neurons.

  • Genetic studies have revealed the in vivo functions of PSD-95 family scaffolds. In addition to learning and memory, PSD-95 family proteins are now implicated in the organization of cholinergic synapses, visual processing, pain perception and behavioural responses to drugs of abuse.

  • GRIP/ABP and PICK1 are PDZ proteins that bind directly to AMPA receptors and regulate their trafficking. With seven PDZ domains, GRIP interacts with numerous proteins, some of which (such as Eph receptors) might also regulate synaptic function. PICK1 also binds to a variety of membrane and cytoplasmic proteins, including kainate receptors.

  • PDZ scaffolds function in motor trafficking of their associated protein complexes. Several PDZ proteins bind directly to motor proteins of the kinesin and myosin families. In this way, PDZ scaffolds on the surface of vesicles can act as 'receptors', linking motors with their specific cargoes.

  • PDZ-based interactions are post-translationally regulated to allow controlled assembly or disassembly of synaptic protein complexes. For instance, AMPA-receptor interactions with GRIP are disrupted by phosphorylation of the C-terminal peptide of GluR2, which is correlated with internalization of AMPA receptors and synaptic depression.

  • With increasing knowledge of the structure and in vivo functions of synaptic PDZ proteins, PDZ interactions could become plausible targets for pharmaceutical intervention, thereby opening up a wealth of possibilities for the treatment of brain diseases.

Abstract

PDZ domains are protein-interaction domains that are often found in multi-domain scaffolding proteins. PDZ-containing scaffolds assemble specific proteins into large molecular complexes at defined locations in the cell. In the postsynaptic density of neuronal excitatory synapses, PDZ proteins such as PSD-95 organize glutamate receptors and their associated signalling proteins and determine the size and strength of synapses. PDZ scaffolds also function in the dynamic trafficking of synaptic proteins by assembling cargo complexes for transport by molecular motors. As key organizers that control synaptic protein composition and structure, PDZ scaffolds are themselves highly regulated by synthesis and degradation, subcellular distribution and post-translational modification.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Three-dimensional structure of PDZ domains.
Figure 2: Schematic diagram of PDZ proteins.
Figure 3: A schematic diagram of the organization of PDZ proteins at a mammalian excitatory synapse.

Similar content being viewed by others

References

  1. Hung, A. Y. & Sheng, M. PDZ domains: structural modules for protein complex assembly. J. Biol. Chem. 277, 5699–5702 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Montgomery, J. M., Zamorano, P. L. & Garner, C. C. MAGUKs in synapse assembly and function: an emerging view. Cell. Mol. Life Sci. 61, 911–929 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. McGee, A. W. & Bredt, D. S. Assembly and plasticity of the glutamatergic postsynaptic specialization. Curr. Opin. Neurobiol. 13, 111–118 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Sheng, M. & Sala, C. PDZ domains and the organization of supramolecular complexes. Annu. Rev. Neurosci. 24, 1–29 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Sheng, M. & Kim, M. J. Postsynaptic signaling and plasticity mechanisms. Science 298, 776–780 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. McGee, A. W. et al. Structure of the SH3-guanylate kinase module from PSD-95 suggests a mechanism for regulated assembly of MAGUK scaffolding proteins. Mol. Cell 8, 1291–1301 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Tavares, G. A., Panepucci, E. H. & Brunger, A. T. Structural characterization of the intramolecular interaction between the SH3 and guanylate kinase domains of PSD-95. Mol. Cell 8, 1313–1325 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Long, J. F. et al. Supramodular structure and synergistic target binding of the N-terminal tandem PDZ domains of PSD-95. J. Mol. Biol. 327, 203–214 (2003). The structure of the first two PDZ domains of PSD-95 was determined by NMR, suggesting a model in which the tandem PDZ domains are oriented in a similar direction to promote interaction with pairs of C termini extending from oligomeric membrane receptors or ion channels.

    Article  CAS  PubMed  Google Scholar 

  9. Hsueh, Y. P. & Sheng, M. Requirement of N-terminal cysteines of PSD-95 for PSD-95 multimerization and ternary complex formation, but not for binding to potassium channel Kv1.4. J. Biol. Chem. 274, 532–536 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Christopherson, K. S. et al. Lipid- and protein-mediated multimerization of PSD-95: implications for receptor clustering and assembly of synaptic protein networks. J. Cell Sci. 116, 3213–3219 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Im, Y. J. et al. Crystal structure of GRIP1 PDZ6-peptide complex reveals the structural basis for class II PDZ target recognition and PDZ domain-mediated multimerization. J. Biol. Chem. 278, 8501–8507 (2002).

    Article  PubMed  CAS  Google Scholar 

  12. Valtschanoff, J. G. & Weinberg, R. J. Laminar organization of the NMDA receptor complex within the postsynaptic density. J. Neurosci. 21, 1211–1217 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Petersen, J. D. et al. Distribution of postsynaptic density (PSD)-95 and Ca2+/calmodulin-dependent protein kinase II at the PSD. J. Neurosci. 23, 11270–11278 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kim, E., Niethammer, M., Rothschild, A., Jan, Y. N. & Sheng, M. Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases. Nature 378, 85–88 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Gramates, L. S. & Budnik, V. Assembly and maturation of the Drosophila larval neuromuscular junction. Int. Rev. Neurobiol. 43, 93–117 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Migaud, M. et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396, 433–439 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Sprengel, R. et al. Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell 92, 279–289 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Passafaro, M., Sala, C., Niethammer, M. & Sheng, M. Microtubule binding by CRIPT and its potential role in the synaptic clustering of PSD-95. Nature Neurosci. 2, 1063–1069 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Steigerwald, F. et al. C-terminal truncation of NR2A subunits impairs synaptic but not extrasynaptic localization of NMDA receptors. J. Neurosci. 20, 4573–4581 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Prybylowski, K. et al. Relationship between availability of NMDA receptor subunits and their expression at the synapse. J. Neurosci. 22, 8902–8910 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Barria, A. & Malinow, R. Subunit-specific NMDA receptor trafficking to synapses. Neuron 35, 345–353 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Mori, H. et al. Role of the carboxy-terminal region of the GluR ε2 subunit in synaptic localization of the NMDA receptor channel. Neuron 21, 571–580 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Roche, K. W. et al. Molecular determinants of NMDA receptor internalization. Nature Neurosci. 4, 794–802 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Jugloff, D. G., Khanna, R., Schlichter, L. C. & Jones, O. T. Internalization of the Kv1.4 potassium channel is suppressed by clustering interactions with PSD-95. J. Biol. Chem. 275, 1357–1364 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Hu, L. A. et al. β1-adrenergic receptor association with PSD-95. Inhibition of receptor internalization and facilitation of β1-adrenergic receptor interaction with N-methyl-D-aspartate receptors. J. Biol. Chem. 275, 38659–38666 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Irie, M. et al. Binding of neuroligins to PSD-95. Science 277, 1511–1515 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Biederer, T. et al. SynCAM, a synaptic adhesion molecule that drives synapse assembly. Science 297, 1525–1531 (2002). This paper identifies SynCAM, a homophilic cell-adhesion molecule of the immunoglobulin superfamily located on both sides of the synapse, which promotes synapse formation by interacting with cytoplasmic PDZ proteins.

    Article  CAS  PubMed  Google Scholar 

  28. Dean, C. et al. Neurexin mediates the assembly of presynaptic terminals. Nature Neurosci. 6, 708–716 (2003). This paper reports that the neuroligin–β-neurexin complex induces presynaptic assembly by two steps: clustering of presynaptic β-neurexin by interaction with oligomeric neuroligin, and recruitment of presynaptic molecules through the PDZ-binding C terminus of β-neurexin.

    Article  CAS  PubMed  Google Scholar 

  29. Hsueh, Y. P. et al. Direct interaction of CASK/LIN-2 and syndecan heparan sulfate proteoglycan and their overlapping distribution in neuronal synapses. J. Cell. Biol. 142, 139–151 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li, Z. & Sheng, M. Some assembly required: the development of neuronal synapses. Nature Rev. Mol. Cell Biol. 4, 833–841 (2003).

    Article  CAS  Google Scholar 

  31. Packard, M., Mathew, D. & Budnik, V. FASt remodeling of synapses in Drosophila. Curr. Opin. Neurobiol. 13, 527–534 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Nehring, R. B. et al. Neuronal inwardly rectifying K+ channels differentially couple to PDZ proteins of the PSD-95/SAP90 family. J. Neurosci. 20, 156–162 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Brenman, J. E. et al. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and α1-syntrophin mediated by PDZ domains. Cell 84, 757–767 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Aarts, M. et al. Treatment of ischemic brain damage by perturbing NMDA receptor–PSD-95 protein interactions. Science 298, 846–850 (2002). A synthetic peptide that mimics the PDZ-binding C terminus of an NMDAR subunit (NR2B) blocks NMDA-induced excitotoxicity without affecting NMDAR function, suggesting the therapeutic potential of this approach in stroke treatment.

    Article  CAS  PubMed  Google Scholar 

  35. Chen, H. J., Rojas-Soto, M., Oguni, A. & Kennedy, M. B. A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron 20, 895–904 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Kim, J. H., Liao, D., Lau, L. F. & Huganir, R. L. SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron 20, 683–691 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Oh, J. S., Manzerra, P. & Kennedy, M. B. Regulation of the neuron-specific Ras GTPase-activating protein, synGAP, by Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 279, 17980–17988 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Zhu, J. J., Qin, Y., Zhao, M., Van Aelst, L. & Malinow, R. Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110, 443–455 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Komiyama, N. H. et al. SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. J. Neurosci. 22, 9721–9732 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kim, J. H., Lee, H. K., Takamiya, K. & Huganir, R. L. The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity. J. Neurosci. 23, 1119–1124 (2003). References 39 and 40, studies on SynGAP-deficient mice, report that SynGAP, a PSD-95-binding GAP for Ras, regulates the MAP kinase pathway, synaptic AMPAR clustering, LTP and spatial learning.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Colledge, M. et al. Targeting of PKA to glutamate receptors through a MAGUK–AKAP complex. Neuron 27, 107 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Tavalin, S. J. et al. Regulation of GluR1 by the A-kinase anchoring protein 79 (AKAP79) signaling complex shares properties with long-term depression. J. Neurosci. 22, 3044–3051 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ehlers, M. D. Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 28, 511–525 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Lee, H. K., Barbarosie, M., Kameyama, K., Bear, M. F. & Huganir, R. L. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Kameyama, K., Lee, H. K., Bear, M. F. & Huganir, R. L. Involvement of a postsynaptic protein kinase A substrate in the expression of homosynaptic long-term depression. Neuron 21, 1163–1175 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Salter, M. W. & Kalia, L. V. Src kinases: a hub for NMDA receptor regulation. Nature Rev. Neurosci. 5, 317–328 (2004).

    Article  CAS  Google Scholar 

  47. Ahmadian, G. et al. Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD. EMBO J. 23, 1040–1050 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kalia, L. V. & Salter, M. W. Interactions between Src family protein tyrosine kinases and PSD-95. Neuropharmacology 45, 720–728 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Tezuka, T., Umemori, H., Akiyama, T., Nakanishi, S. & Yamamoto, T. PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A. Proc. Natl Acad. Sci. USA 96, 435–440 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Huang, Y. et al. CAKβ/Pyk2 kinase is a signaling link for induction of long-term potentiation in CA1 hippocampus. Neuron 29, 485–496 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Hering, H. & Sheng, M. Dendritic spines: structure, dynamics and regulation. Nature Rev. Neurosci. 2, 880–888 (2001).

    Article  CAS  Google Scholar 

  52. Bonhoeffer, T. & Yuste, R. Spine motility. Phenomenology, mechanisms, and function. Neuron 35, 1019–1027 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Penzes, P. et al. The neuronal Rho-GEF Kalirin-7 interacts with PDZ domain-containing proteins and regulates dendritic morphogenesis. Neuron 29, 229–242 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Penzes, P. et al. Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 37, 263–274 (2003). Activation of EphB receptors by their ephrinB ligand stimulates Kalirin-7, a PSD-95-binding guanine nucleotide exchange factor (GEF) for Rac1, and promotes spine formation through a signalling pathway that involves Rac1 and PAK.

    Article  CAS  PubMed  Google Scholar 

  55. Takasu, M. A., Dalva, M. B., Zigmond, R. E. & Greenberg, M. E. Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science 295, 491–495 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Peng, J. et al. Semiquantitative proteomic analysis of rat forebrain postsynaptic density fractions by mass spectrometry. J. Biol. Chem. 217, 21003–21011 (2004). As well as identifying approximately 400 proteins in the PSD fraction, this paper uses quantitative mass spectrometry to measure the relative abundance in molar terms of key proteins of the PSD, including PSD-95, GKAP, Shank1, NMDAR (NR1) and AMPAR (GluR1 and GluR2).

    Article  CAS  Google Scholar 

  57. Pak, D. T. & Sheng, M. Targeted protein degradation and synapse remodeling by an inducible protein kinase. Science 302, 1368–1373 (2003). SNK, a protein kinase induced by synaptic activity, binds to and phosphorylates SPAR, a postsynaptic GAP for the small GTPase Rap, leading to degradation of SPAR by the ubiquitin–proteasome pathway, and resulting in activity-dependent loss of synapses and spines.

    Article  CAS  PubMed  Google Scholar 

  58. El-Husseini, A. E., Schnell, E., Chetkovich, D. M., Nicoll, R. A. & Bredt, D. S. PSD-95 involvement in maturation of excitatory synapses. Science 290, 1364–1368 (2000).

    CAS  PubMed  Google Scholar 

  59. Sheng, M. & Kim, E. The Shank family of scaffold proteins. J. Cell Sci. 113, 1851–1856 (2000).

    CAS  PubMed  Google Scholar 

  60. Cho, K. O., Hunt, C. A. & Kennedy, M. B. The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein. Neuron 9, 929–942 (1992).

    Article  CAS  PubMed  Google Scholar 

  61. Stein, V., House, D. R., Bredt, D. S. & Nicoll, R. A. Postsynaptic density-95 mimics and occludes hippocampal long-term potentiation and enhances long-term depression. J. Neurosci. 23, 5503–5506 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Beique, J. C. & Andrade, R. PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex. J. Physiol. 546, 859–867 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Ehrlich, I. & Malinow, R. Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity. J. Neurosci. 24, 916–927 (2004). References 61–63 demonstrate a central role for PSD-95 in the control of synaptic abundance of AMPARs and synaptic plasticity based on electrophysiological experiments in brain slices transfected with PSD-95 constructs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Chen, L. et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943 (2000). Stargazin, an AMPAR- and PSD-95-associated membrane protein, is shown to promote synaptic AMPAR targeting by two distinct mechanisms: surface expression and synaptic targeting.

    Article  CAS  PubMed  Google Scholar 

  65. Schnell, E. et al. Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proc. Natl Acad. Sci. USA 99, 13902–13907 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yao, W. D. et al. Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity. Neuron 41, 625–638 (2004). Using gene-expression profiling and PSD-95-deficient mice, this paper implicates changes in the level of PSD-95 in psychostimulant action and addiction to drugs of abuse.

    Article  CAS  PubMed  Google Scholar 

  67. Craven, S. E., El-Husseini, A. E. & Bredt, D. S. Synaptic targeting of the postsynaptic density protein PSD-95 mediated by lipid and protein motifs. Neuron 22, 497–509 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. El-Husseini Ael, D. et al. Synaptic strength regulated by palmitate cycling on PSD-95. Cell 108, 849–863 (2002). This paper reports that palmitoylation and depalmitoylation of PSD-95 regulate the synaptic localization of PSD-95, and consequently of AMPARs, in an activity-dependent manner.

    Article  Google Scholar 

  69. Colledge, M. et al. Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 40, 595–607 (2003). The authors provide evidence that synaptic activity rapidly breaks down PSD-95 via the ubiquitin–proteasome pathway and that this degradation is required for activity-induced internalization of synaptic AMPARs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Morabito, M. A., Sheng, M. & Tsai, L. H. Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons. J. Neurosci. 24, 865–876 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Mauceri, D., Cattabeni, F., Di Luca, M. & Gardoni, F. CaMKII-dependent phosphorylation drives synapse-associated protein 97 into spines. J. Biol. Chem. 279, 23813–23821 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Koh, Y. H., Popova, E., Thomas, U., Griffith, L. C. & Budnik, V. Regulation of DLG localization at synapses by CaMKII-dependent phosphorylation. Cell 98, 353–363 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Inoue, A. & Okabe, S. The dynamic organization of postsynaptic proteins: translocating molecules regulate synaptic function. Curr. Opin. Neurobiol. 13, 332–340 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Fagiolini, M. et al. Separable features of visual cortical plasticity revealed by N-methyl-D-aspartate receptor 2A signaling. Proc. Natl Acad. Sci. USA 100, 2854–2859 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tao, Y. X. et al. Impaired NMDA receptor-mediated postsynaptic function and blunted NMDA receptor-dependent persistent pain in mice lacking postsynaptic density-93 protein. J. Neurosci. 23, 6703–6712 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Conroy, W. G., Liu, Z., Nai, Q., Coggan, J. S. & Berg, D. K. PDZ-containing proteins provide a functional postsynaptic scaffold for nicotinic receptors in neurons. Neuron 38, 759–771 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Parker, M. J., Zhao, S., Bredt, D. S., Sanes, J. R. & Feng, G. PSD93 regulates synaptic stability at neuronal cholinergic synapses. J. Neurosci. 24, 378–388 (2004). References 76 and 77 identify PSD-93 as being important for the structure and functions of neuronal cholinergic synapses, in addition to glutamatergic synapses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. El-Husseini, A. E. et al. Ion channel clustering by membrane-associated guanylate kinases. Differential regulation by N-terminal lipid and metal binding motifs. J. Biol. Chem. 275, 23904–23910 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Valtschanoff, J. G. et al. SAP97 concentrates at the postsynaptic density in cerebral cortex. Eur. J. Neurosci. 12, 3605–3614 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Sans, N. et al. Synapse-associated protein 97 selectively associates with a subset of AMPA receptors early in their biosynthetic pathway. J. Neurosci. 21, 7506–7516 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Rumbaugh, G., Sia, G. M., Garner, C. C. & Huganir, R. L. Synapse-associated protein-97 isoform-specific regulation of surface AMPA receptors and synaptic function in cultured neurons. J. Neurosci. 23, 4567–4576 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sans, N. et al. A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J. Neurosci. 20, 1260–1271 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Townsend, M., Yoshii, A., Mishina, M. & Constantine-Paton, M. Developmental loss of miniature N-methyl-D-aspartate receptor currents in NR2A knockout mice. Proc. Natl Acad. Sci. USA 100, 1340–1345 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Losi, G. et al. PSD-95 regulates NMDA receptors in developing cerebellar granule neurons of the rat. J. Physiol. 548, 21–29 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Dakoji, S., Tomita, S., Karimzadegan, S., Nicoll, R. A. & Bredt, D. S. Interaction of transmembrane AMPA receptor regulatory proteins with multiple membrane associated guanylate kinases. Neuropharmacology 45, 849–856 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Leonard, A. S., Davare, M. A., Horne, M. C., Garner, C. C. & Hell, J. W. SAP97 is associated with the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit. J. Biol. Chem. 273, 19518–19524 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Bredt, D. S. & Nicoll, R. A. AMPA receptor trafficking at excitatory synapses. Neuron 40, 361–379 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Feng, W., Shi, Y., Li, M. & Zhang, M. Tandem PDZ repeats in glutamate receptor-interacting proteins have a novel mode of PDZ domain-mediated target binding. Nature Struct. Biol. 10, 972–978 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Bruckner, K. et al. EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft membrane microdomains. Neuron 22, 511–524 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Ye, B. et al. GRASP-1: a neuronal RasGEF associated with the AMPA receptor/GRIP complex. Neuron 26, 603–617 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Wyszynski, M. et al. Interaction between GRIP and liprin-a/SYD2 required for AMPA receptor targeting. Neuron 34, 39–52 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Takamiya, K. et al. A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1. Nature Genet. 36, 172–177 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Hirbec, H. et al. Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP. Neuron 37, 625–638 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bladt, F., Tafuri, A., Gelkop, S., Langille, L. & Pawson, T. Epidermolysis bullosa and embryonic lethality in mice lacking the multi-PDZ domain protein GRIP1. Proc. Natl Acad. Sci. USA 99, 6816–6821 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. DeSouza, S., Fu, J., States, B. A. & Ziff, E. B. Differential palmitoylation directs the AMPA receptor-binding protein ABP to spines or to intracellular clusters. J. Neurosci. 22, 3493–3503 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Fu, J., deSouza, S. & Ziff, E. B. Intracellular membrane targeting and suppression of Ser880 phosphorylation of glutamate receptor 2 by the linker I-set II domain of AMPA receptor-binding protein. J. Neurosci. 23, 7592–7601 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wyszynski, M. et al. Association of AMPA receptors with a subset of glutamate receptor-interacting protein in vivo. J. Neurosci. 19, 6528–6537 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Contractor, A. et al. Trans-synaptic Eph receptor-ephrin signaling in hippocampal mossy fiber LTP. Science 296, 1864–1869 (2002). This paper shows that the PDZ interaction of EphB receptors with GRIP and trans-synaptic interactions between B-ephrins and EphB receptors are important for the induction of mossy fibre LTP in the CA3 area of the hippocampus.

    Article  CAS  PubMed  Google Scholar 

  100. Grunwald, I. C. et al. Hippocampal plasticity requires postsynaptic ephrinBs. Nature Neurosci. 7, 33–40 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Williams, M. E., Wu, S. C., McKenna, W. L. & Hinck, L. Surface expression of the netrin receptor UNC5H1 is regulated through a protein kinase C-interacting protein/protein kinase-dependent mechanism. J. Neurosci. 23, 11279–11288 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Perroy, J. et al. PICK1 is required for the control of synaptic transmission by the metabotropic glutamate receptor 7. EMBO J. 21, 2990–2999 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hirbec, H. et al. The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs. J. Biol. Chem. 277, 15221–15224 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Torres, G. E. et al. Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1. Neuron 30, 121–134 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Jaulin-Bastard, F. et al. The ERBB2/HER2 receptor differentially interacts with ERBIN and PICK1 PSD-95/DLG/ZO-1 domain proteins. J. Biol. Chem. 276, 15256–15263 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Braithwaite, S. P., Xia, H. & Malenka, R. C. Differential roles for NSF and GRIP/ABP in AMPA receptor cycling. Proc. Natl Acad. Sci. USA 99, 7096–7101 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chung, H. J., Steinberg, J. P., Huganir, R. L. & Linden, D. J. Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science 300, 1751–1755 (2003). By rescue experiments in GluR2-deficient Purkinje cell cultures, the authors show that phosphorylation of Ser880 in GLUR2 is required for the induction of cerebellar LTD.

    Article  CAS  PubMed  Google Scholar 

  108. Daw, M. I. et al. PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses. Neuron 28, 873–886 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Kim, C. H., Chung, H. J., Lee, H. K. & Huganir, R. L. Interaction of the AMPA receptor subunit GluR2/3 with PDZ domains regulates hippocampal long-term depression. Proc. Natl Acad. Sci. USA 98, 11725–11730 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Seidenman, K. J., Steinberg, J. P., Huganir, R. & Malinow, R. Glutamate receptor subunit 2 Serine 880 phosphorylation modulates synaptic transmission and mediates plasticity in CA1 pyramidal cells. J. Neurosci. 23, 9220–9228 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Mok, H. et al. Association of the kinesin superfamily motor protein KIF1Bα with postsynaptic density-95 (PSD-95), synapse-associated protein-97, and synaptic scaffolding molecule PSD-95/discs large/zona occludens-1 proteins. J. Neurosci. 22, 5253–5258 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Asaba, N., Hanada, T., Takeuchi, A. & Chishti, A. H. Direct interaction with a kinesin-related motor mediates transport of mammalian discs large tumor suppressor homologue in epithelial cells. J. Biol. Chem. 278, 8395–8400 (2002).

    Article  PubMed  CAS  Google Scholar 

  113. Wu, H., Nash, J. E., Zamorano, P. & Garner, C. C. Interaction of SAP97 with minus-end-directed actin motor myosin VI. Implications for AMPA receptor trafficking. J. Biol. Chem. 277, 30928–30934 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Naisbitt, S. et al. Interaction of the postsynaptic density-95/guanylate kinase domain-associated protein complex with a light chain of myosin-V and dynein. J. Neurosci. 20, 4524–4534 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sans, N. et al. NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex. Nature Cell Biol. 5, 520–530 (2003). This paper reports that Sec8, a component of the exocyst complex, associates with SAP102, a member of the PSD-95 family, and regulates the surface expression and synaptic localization of the NMDARs.

    Article  CAS  PubMed  Google Scholar 

  116. Kaech, S. M., Whitfield, C. W. & Kim, S. K. The LIN-2/LIN-7/LIN-10 complex mediates basolateral membrane localization of the C. elegans EGF receptor LET-23 in vulval epithelial cells. Cell 94, 761–771 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Rongo, C., Whitfield, C. W., Rodal, A., Kim, S. K. & Kaplan, J. M. LIN-10 is a shared component of the polarized protein localization pathways in neurons and epithelia. Cell 94, 751–759 (1998).

    Article  CAS  PubMed  Google Scholar 

  118. Setou, M., Nakagawa, T., Seog, D. H. & Hirokawa, N. Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science 288, 1796–1802 (2000). The KIF17 kinesin motor is shown to interact with the PDZ1 domain of LIN10 and to transport the LIN2/LIN7/LIN10/NMDAR complex to synapses, suggesting that PDZ proteins can function as receptors that link motors to their specific cargoes.

    Article  CAS  PubMed  Google Scholar 

  119. Ho, A., Morishita, W., Hammer, R. E., Malenka, R. C. & Sudhof, T. C. A role for Mints in transmitter release: Mint 1 knockout mice exhibit impaired GABAergic synaptic transmission. Proc. Natl Acad. Sci. USA 100, 1409–1414 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hsueh, Y. P., Wang, T. F., Yang, F. C. & Sheng, M. Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Nature 404, 298–302 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Wang, G. S. et al. Transcriptional modification by a CASK-interacting nucleosome assembly protein. Neuron 42, 113–128 (2004).

    Article  CAS  PubMed  Google Scholar 

  122. Setou, M. et al. Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites. Nature 417, 83–87 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. Shin, H. et al. Association of the kinesin motor KIF1A with the multimodular protein liprin-α. J. Biol. Chem. 278, 11393–11401 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Tanemoto, M., Fujita, A., Higashi, K. & Kurachi, Y. PSD-95 mediates formation of a functional homomeric Kir5.1 channel in the brain. Neuron 34, 387–397 (2002).

    Article  CAS  PubMed  Google Scholar 

  125. Hu, L. A., Chen, W., Premont, R. T., Cong, M. & Lefkowitz, R. J. G protein-coupled receptor kinase 5 regulates β1-adrenergic receptor association with PSD-95. J. Biol. Chem. 277, 1607–1613 (2002).

    Article  CAS  PubMed  Google Scholar 

  126. Choi, J. et al. Phosphorylation of stargazin by protein kinase A regulates its interaction with PSD-95. J. Biol. Chem. 277, 12359–12363 (2002).

    Article  CAS  PubMed  Google Scholar 

  127. Chetkovich, D. M., Chen, L., Stocker, T. J., Nicoll, R. A. & Bredt, D. S. Phosphorylation of the postsynaptic density-95 (PSD-95)/discs large/zona occludens-1 binding site of stargazin regulates binding to PSD-95 and synaptic targeting of AMPA receptors. J. Neurosci. 22, 5791–5796 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Perez, J. L. et al. PICK1 targets activated protein kinase Cα to AMPA receptor clusters in spines of hippocampal neurons and reduces surface levels of the AMPA-type glutamate receptor subunit 2. J. Neurosci. 21, 5417–5428 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Gardoni, F. et al. The NMDA receptor complex is altered in an animal model of human cerebral heterotopia. J. Neuropathol. Exp. Neurol. 62, 662–675 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Doyle, D. A. et al. Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ. Cell 85, 1067–1076 (1996).

    Article  CAS  PubMed  Google Scholar 

  131. Kornau, H. C., Schenker, L. T., Kennedy, M. B. & Seeburg, P. H. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269, 1737–1740 (1995).

    Article  CAS  PubMed  Google Scholar 

  132. Garcia, E. P. et al. SAP90 binds and clusters kainate receptors causing incomplete desensitization. Neuron 21, 727–739 (1998).

    Article  CAS  PubMed  Google Scholar 

  133. Roche, K. W. et al. Postsynaptic density-93 interacts with the δ2 glutamate receptor subunit at parallel fiber synapses. J. Neurosci. 19, 3926–3934 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Becamel, C. et al. The serotonin 5-HT2A and 5-HT2C receptors interact with specific sets of PDZ proteins. J. Biol. Chem. 279, 20257–20266 (2004).

    Article  CAS  PubMed  Google Scholar 

  135. Garcia, R. A., Vasudevan, K. & Buonanno, A. The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses. Proc. Natl Acad. Sci. USA 97, 3596–3601 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Huang, Y. Z. et al. Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses. Neuron 26, 443–455 (2000).

    Article  CAS  PubMed  Google Scholar 

  137. Akum, B. F. et al. Cypin regulates dendrite patterning in hippocampal neurons by promoting microtubule assembly. Nature Neurosci. 7, 145–152 (2004).

    Article  CAS  PubMed  Google Scholar 

  138. Seabold, G. K., Burette, A., Lim, I. A., Weinberg, R. J. & Hell, J. W. Interaction of the tyrosine kinase Pyk2 with the N-methyl-D-aspartate receptor complex via the Src homology 3 domains of PSD-95 and SAP102. J. Biol. Chem. 278, 15040–15048 (2003).

    Article  CAS  PubMed  Google Scholar 

  139. Kim, E. et al. GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules. J. Cell. Biol. 136, 669–678 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Chetkovich, D. M. et al. Postsynaptic targeting of alternative postsynaptic density-95 isoforms by distinct mechanisms. J. Neurosci. 22, 6415–6425 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Lee, S., Fan, S., Makarova, O., Straight, S. & Margolis, B. A novel and conserved protein–protein interaction domain of mammalian Lin-2/CASK binds and recruits SAP97 to the lateral surface of epithelia. Mol. Cell Biol. 22, 1778–1791 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Feng, J. et al. Spinophilin regulates the formation and function of dendritic spines. Proc. Natl Acad. Sci. USA 97, 9287–9292 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Takai, Y. & Nakanishi, H. Nectin and afadin: novel organizers of intercellular junctions. J. Cell Sci. 116, 17–27 (2003).

    Article  CAS  PubMed  Google Scholar 

  144. Walikonis, R. S. et al. Densin-180 forms a ternary complex with the α-subunit of Ca2+/calmodulin-dependent protein kinase II and α-actinin. J. Neurosci. 21, 423–433 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kolch, W. Erbin: sorting out ErbB2 receptors or giving Ras a break? Sci. STKE, pe37 (2003).

  146. Sala, C. et al. Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 31, 115–130 (2001).

    Article  CAS  PubMed  Google Scholar 

  147. Kitano, J. et al. Tamalin is a scaffold protein that interacts with multiple neuronal proteins in distinct modes of protein–protein association. J. Biol. Chem. 278, 14762–14768 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Feng Wei and Mingjie Zhang (Hong Kong University of Science and Technology) for providing the PDZ domain structures for figure 1.

Author information

Authors and Affiliations

  1. National Creative Research Initiative Center for Synaptogenesis and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Guseong-dong, Yuseong-gu, 305-701, Daejeon, Korea

    Eunjoon Kim

  2. The Picower Center for Learning and Memory, RIKEN-MIT Neuroscience Research Center, Howard Hughes Medical Institute, Massachusetts Institute of Technology, 77 Massachusetts Avenue (E18-215), Cambridge, 02139, Massachusetts, USA

    Morgan Sheng

Authors
  1. Eunjoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Morgan Sheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

CASK

CDK5

Dlg

ErbB2

GKAP

GluR1

Homer

PICK1

PSD-95

SAP97

Shank

SPAR

Src

syndecan

FURTHER INFORMATION

Encyclopedia of Life Sciences

AMPA receptors

Dendritic spines

Long-term depression and depotentiation

Long-term potentiation

NMDA receptors

Glossary

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. It can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD-95, discs large, zona occludens 1).

POSTSYNAPTIC DENSITY

An electron-dense specialization of excitatory postsynaptic membranes that contains a high concentration of glutamate receptors and associated signalling and cytoskeletal proteins.

SRC HOMOLOGY 3 DOMAIN

(SH3 domain). A protein–protein interaction domain that binds to PXXP or related peptide sequences.

GUANYLATE KINASE-LIKE DOMAIN

(GK domain). A protein–protein interaction domain found in the membrane-associated guanylate kinase (MAGUK) superfamily of proteins, which includes PSD-95 and related proteins.

RAS, RAP AND RAC

Small monomeric G-proteins that, in their activated GTP-bound state, interact with and stimulate their downstream effectors. Hydrolysis of bound GTP by the intrinsic GTPase activity of these proteins terminates their activity. Guanine nucleotide exchange factors (GEFs) stimulate GTP loading and activate these small G-proteins; GTPase-activating proteins (GAPs) inhibit their activity.

LONG-TERM POTENTIATION

(LTP). A long-lasting enhancement of synaptic strength that is elicited by specific patterns of synaptic stimulation (for example, high frequency tetanus). Typically dependent on NMDA-receptor activation, and widely believed to be a means of information storage in the brain.

DENDRITIC SPINES

Tiny actin-rich protrusions from the dendrite that form the postsynaptic compartment for most excitatory synapses in the brain.

RNA INTERFERENCE

(RNAi). A method for suppressing the expression of a specific protein based on targeted hybridization of small interfering RNAs to the mRNA encoding that protein.

LONG-TERM DEPRESSION

(LTD). A long-lasting suppression of synaptic strength that is elicited by specific patterns of synaptic stimulation (for example, low frequency stimulation). Typically dependent on NMDA-receptor activation, and widely believed to be a means of information storage in the brain.

KINESINS

A large family of structurally related motor proteins that use ATP to transport specific cargoes along microtubules.

MYOSINS

A large family of structurally related motor proteins that use ATP to transport specific cargoes along actin filaments.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, E., Sheng, M. PDZ domain proteins of synapses. Nat Rev Neurosci 5, 771–781 (2004). https://doi.org/10.1038/nrn1517

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1517

This article is cited by

Search

Advanced 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