Abstract
CRIPT is a postsynaptic protein that binds selectively to the third PDZ domain (PDZ3) of PSD-95. Here we show that CRIPT also binds directly to microtubules, thereby linking PSD-95 to the microtubule cytoskeleton. Disrupting the CRIPT–PSD-95 interaction in cultured hippocampal neurons with a PDZ3-specific peptide prevented the association of PSD-95 with microtubules and inhibited the synaptic clustering of PSD-95, chapsyn-110/PSD-93 and GKAP (a PSD-95-binding protein). However, the number of synapses and the synaptic clustering of NMDA receptors were unaffected, suggesting that PSD-95-family proteins are not essential for the maintenance of synapses and the synaptic localization of NMDA receptors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Anderson, J. M. Cell signalling: MAGUK magic. Curr. Biol. 6, 382–384 (1996).
Sheng, M. PDZs and receptor/channel clustering: rounding up the latest suspects. Neuron 17, 575–578 (1996).
Sheng, M. & Wyszynski, M. Ion channel targeting in neurons. Bioessays 19, 847–853 (1997).
Kornau, H. C., Seeburg, P. H. & Kennedy, M. B. Interaction of ion channels and receptors with PDZ domain proteins. Curr. Opin. Neurobiol. 7, 368–373 (1997).
Ziff, E. B. Enlightening the postsynaptic density. Neuron 19, 1163–1174 (1997).
Craven, S. E. & Bredt, D. S. PDZ proteins organize synaptic signaling pathways. Cell 93, 495–498 (1998).
O'Brien, R., Lau, L. T. & Huganir, R. L. Molecular mechanisms of glutamate receptor clustering at excitatory synapses. Curr. Opin. Neurobiol. 8, 364–369 (1998).
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).
Niethammer, M., Kim, E. & Sheng, M. Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases. J. Neurosci. 16, 2157–2163 (1996).
Sprengel, R. et al. Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell 92, 279–289 (1998).
Mori, H. et al. Role of the carboxy-terminal region of the GluR epsilon2 subunit in synaptic localization of the NMDA receptor channel. Neuron 21, 571–580 (1998).
Migaud, M. et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396, 433–439 (1998).
Wyszynski, M. et al. Competitive binding of alpha-actinin and calmodulin to the NMDA receptor. Nature 385, 439–442 (1997).
Ehlers, M. D., Fung, E. L., O'Brien, R. J. & Huganir, R. L. Splice variant-specific interaction of the NMDA receptor subunit NR1 with neuronal intermediate filaments. J. Neurosci. 18, 720–730 (1998).
Lin, J. W. et al. Yotiao, a novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1. J. Neurosci. 18, 2017–2027 (1998).
Wechsler, A. & Teichberg, V. Brain spectrin binding to the NMDA receptor is regulated by phosphorylation, calcium and calmodulin. EMBO J. 17, 3931–3939 (1998).
Niethammer, M. et al. CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90. Neuron 20, 693–707 (1998).
Prochiantz, A. Getting hydrophilic compounds into cells: lessons from homeopeptides. Curr. Opin. Neurobiol. 6, 629–634 (1996).
Cohen, A. R. et al. Human Cask/Lin-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells. J. Cell Biol. 142, 129–138 (1998).
Colledge, M. & Froehner, S. C. Signals mediating ion channel clustering at the neuromuscular junction. Curr. Opin. Neurobiol. 8, 357–363 (1998).
Kuhse, J., Betz, H. & Kirsch, J. The inhibitory glycine receptor: architecture, synaptic localization and molecular pathology of a postsynaptic ion-channel complex. Curr. Opin. Neurobiol. 5, 318–323 (1995).
Brenman, J. E. et al. Localization of postsynaptic density-93 to dendritic microtubules and interaction with microtubule-associated protein 1A. J. Neurosci. 18, 8805–8813 (1998).
Irie, M. et al. Binding of neuroligins to PSD-95. Science 277, 1511–1515 (1997).
Missler, M., Fernandez-Chacon, R. & Sudhof, T. C. The making of neurexins. J. Neurochem. 71, 1339–1347 (1998).
Zhang, W., Vasquez, L., Apperson, M. & Kennedy, M. B. Citron binds to PSD-95 at glutamatergic synapses on inhibitory neurons in the hippocampus. J. Neurosci. 19, 96–108 (1999).
Furuyashiki, T. et al. Citron, a rho-target, interacts with PSD-95/SAP-90 at glutamatergic synapses in the thalamus. J. Neurosci. 19, 109–118 (1999).
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).
Arnold, D. B. & Clapham, D. E. Molecular determinants for subcellular localization of PSD-95 with an interacting K+ channel. Neuron 23, 149–157 (1999).
Hsueh, Y.-P., Kim, E. & Sheng, M. Disulfide-linked head-to-head multimerization in the mechanism of ion channel clustering by PSD-95. Neuron 18, 803–814 (1997).
Harris, K. & Kater, S. Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Annu. Rev. Neurosci. 17, 341–371 (1994).
Kelly, P. T. & Cotman, C. W. Characterization of tubulin and actin and identification of a distinct postsynaptic density polypeptide. J. Cell Biol. 79, 173–183 (1978).
Caceres, A. et al. Differential subcellular localization of tubulin and the microtubule-associated protein MAP2 in brain tissue as revealed by immunocytochemistry with monoclonal hybridoma antibodies. J. Neurosci. 4, 394–410 (1984).
Walsh, M. J. & Kuruc, N. The postsynaptic density: constituent and associated proteins characterized by electrophoresis, immunoblotting and peptide sequencing. J. Neurochem. 59, 667–678 (1992).
Lai, S. L. et al. Characterization of granular particles isolated from postsynaptic densities. J. Neurochem. 71, 1694–1701 (1998).
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).
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).
Brewer, G. J. & Cotman, C. W. Survival and growth of hippocampal neurons in defined medium at low density: advantage of a sandwich culture technique or low oxygen. Brain Res. 494, 65–74 (1989).
Banker, G. A. & Cowan, W. M. Rat hippocampal neurons in dispersed cell culture. Brain Res. 126, 397–425 (1977).
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).
Acknowledgements
M.S. is Assistant Investigator of the Howard Hughes Medical Institute. This work was supported by NIH grant NS35050 to M.S. and by the Armenise-Harvard Foundation (DIBIT-San Raffaele, Italy) to C.S.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Passafaro, M., Sala, C., Niethammer, M. et al. Microtubule binding by CRIPT and its potential role in the synaptic clustering of PSD-95. Nat Neurosci 2, 1063–1069 (1999). https://doi.org/10.1038/15990
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/15990
This article is cited by
-
Identification of candidate genetic variants and altered protein expression in neural stem and mature neural cells support altered microtubule function to be an essential component in bipolar disorder
Translational Psychiatry (2020)
-
Interaction Between CRIPT and PSD-95 Is Required for Proper Dendritic Arborization in Hippocampal Neurons
Molecular Neurobiology (2020)
-
A unique intracellular tyrosine in neuroligin-1 regulates AMPA receptor recruitment during synapse differentiation and potentiation
Nature Communications (2018)
-
GKAP orchestrates activity-dependent postsynaptic protein remodeling and homeostatic scaling
Nature Neuroscience (2012)
-
Copy number variants and infantile spasms: evidence for abnormalities in ventral forebrain development and pathways of synaptic function
European Journal of Human Genetics (2011)