Liprin-α2 Promotes the Presynaptic Recruitment and Turnover of RIM1/CASK to Facilitate Synaptic Transmission

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2013 Jun 12

PMID 23751498

Citations 60

Authors

Samantha A Spangler

Sabine K Schmitz

Josta T Kevenaar

Esther de Graaff

Heidi de Wit

Jeroen Demmers

Ruud F Toonen

Casper C Hoogenraad

Affiliations

Soon will be listed here.

Abstract

The presynaptic active zone mediates synaptic vesicle exocytosis, and modulation of its molecular composition is important for many types of synaptic plasticity. Here, we identify synaptic scaffold protein liprin-α2 as a key organizer in this process. We show that liprin-α2 levels were regulated by synaptic activity and the ubiquitin-proteasome system. Furthermore, liprin-α2 organized presynaptic ultrastructure and controlled synaptic output by regulating synaptic vesicle pool size. The presence of liprin-α2 at presynaptic sites did not depend on other active zone scaffolding proteins but was critical for recruitment of several components of the release machinery, including RIM1 and CASK. Fluorescence recovery after photobleaching showed that depletion of liprin-α2 resulted in reduced turnover of RIM1 and CASK at presynaptic terminals, suggesting that liprin-α2 promotes dynamic scaffolding for molecular complexes that facilitate synaptic vesicle release. Therefore, liprin-α2 plays an important role in maintaining active zone dynamics to modulate synaptic efficacy in response to changes in network activity.

Citing Articles

Intracellular protein-lipid interactions drive presynaptic assembly prior to neurexin recruitment.

Frankel E, Tiroumalechetty A, Su Z, Henry P, Mueller B, Jorgensen E Neuron. 2025; 113(5):737-753.e6.

PMID: 39814011 PMC: 11886894. DOI: 10.1016/j.neuron.2024.12.017.

A Systematic Review of the Molecular and Cellular Alterations Induced by Cannabis That May Serve as Risk Factors for Bipolar Disorder.

Delgado-Sequera A, Garcia-Mompo C, Gonzalez-Pinto A, Hidalgo-Figueroa M, Berrocoso E Int J Neuropsychopharmacol. 2024; 27(2).

PMID: 38175142 PMC: 10863486. DOI: 10.1093/ijnp/pyae002.

Protein-lipid interactions drive presynaptic assembly upstream of cell adhesion molecules.

Frankel E, Tiroumalechetty A, Henry P, Su Z, Wu Y, Kurshan P bioRxiv. 2023; .

PMID: 38014115 PMC: 10680821. DOI: 10.1101/2023.11.17.567618.

Diverse Clinical Phenotypes of -Related Disorders and Multiple Functional Domains of CASK Protein.

Mori T, Zhou M, Tabuchi K Genes (Basel). 2023; 14(8).

PMID: 37628707 PMC: 10454856. DOI: 10.3390/genes14081656.

PTPδ is a presynaptic organizer for the formation and maintenance of climbing fiber to Purkinje cell synapses in the developing cerebellum.

Okuno Y, Sakoori K, Matsuyama K, Yamasaki M, Watanabe M, Hashimoto K Front Mol Neurosci. 2023; 16:1206245.

PMID: 37426069 PMC: 10323364. DOI: 10.3389/fnmol.2023.1206245.

References

Dai Y, Taru H, Deken S, Grill B, Ackley B, Nonet M . SYD-2 Liprin-alpha organizes presynaptic active zone formation through ELKS. Nat Neurosci. 2006; 9(12):1479-87. DOI: 10.1038/nn1808. View

Kim P, Lu L, Xia Y, Gerstein M . Relating three-dimensional structures to protein networks provides evolutionary insights. Science. 2006; 314(5807):1938-41. DOI: 10.1126/science.1136174. View

Matz J, Gilyan A, Kolar A, McCarvill T, Krueger S . Rapid structural alterations of the active zone lead to sustained changes in neurotransmitter release. Proc Natl Acad Sci U S A. 2010; 107(19):8836-41. PMC: 2889309. DOI: 10.1073/pnas.0906087107. View

Owald D, Khorramshahi O, Gupta V, Banovic D, Depner H, Fouquet W . Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly. Nat Neurosci. 2012; 15(9):1219-26. DOI: 10.1038/nn.3183. View

Leal-Ortiz S, Waites C, Terry-Lorenzo R, Zamorano P, Gundelfinger E, Garner C . Piccolo modulation of Synapsin1a dynamics regulates synaptic vesicle exocytosis. J Cell Biol. 2008; 181(5):831-46. PMC: 2396795. DOI: 10.1083/jcb.200711167. View

Choe K, Prakash S, Bright A, Clandinin T . Liprin-alpha is required for photoreceptor target selection in Drosophila. Proc Natl Acad Sci U S A. 2006; 103(31):11601-6. PMC: 1544216. DOI: 10.1073/pnas.0601185103. View

Schikorski T, Stevens C . Quantitative fine-structural analysis of olfactory cortical synapses. Proc Natl Acad Sci U S A. 1999; 96(7):4107-12. PMC: 22428. DOI: 10.1073/pnas.96.7.4107. View

Rubinson D, Dillon C, Kwiatkowski A, Sievers C, Yang L, Kopinja J . A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat Genet. 2003; 33(3):401-6. DOI: 10.1038/ng1117. View

Lee S, Valtschanoff J, Kharazia V, Weinberg R, Sheng M . Biochemical and morphological characterization of an intracellular membrane compartment containing AMPA receptors. Neuropharmacology. 2001; 41(6):680-92. DOI: 10.1016/s0028-3908(01)00124-1. View

10.

Fernandez-Alfonso T, Ryan T . The kinetics of synaptic vesicle pool depletion at CNS synaptic terminals. Neuron. 2004; 41(6):943-53. DOI: 10.1016/s0896-6273(04)00113-8. View

11.

Astigarraga S, Hofmeyer K, Farajian R, Treisman J . Three Drosophila liprins interact to control synapse formation. J Neurosci. 2010; 30(46):15358-68. PMC: 2999520. DOI: 10.1523/JNEUROSCI.1862-10.2010. View

12.

van Roessel P, Elliott D, Robinson I, Prokop A, Brand A . Independent regulation of synaptic size and activity by the anaphase-promoting complex. Cell. 2004; 119(5):707-18. DOI: 10.1016/j.cell.2004.11.028. View

13.

Hofmeyer K, Maurel-Zaffran C, Sink H, Treisman J . Liprin-alpha has LAR-independent functions in R7 photoreceptor axon targeting. Proc Natl Acad Sci U S A. 2006; 103(31):11595-600. PMC: 1544215. DOI: 10.1073/pnas.0604766103. View

14.

Tai H, Schuman E . Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction. Nat Rev Neurosci. 2008; 9(11):826-38. DOI: 10.1038/nrn2499. View

15.

Wyszynski M, Kim E, Dunah A, Passafaro M, Valtschanoff J, Serra-Pages C . Interaction between GRIP and liprin-alpha/SYD2 is required for AMPA receptor targeting. Neuron. 2002; 34(1):39-52. DOI: 10.1016/s0896-6273(02)00640-2. View

16.

Patel M, Lehrman E, Poon V, Crump J, Zhen M, Bargmann C . Hierarchical assembly of presynaptic components in defined C. elegans synapses. Nat Neurosci. 2006; 9(12):1488-98. PMC: 3917495. DOI: 10.1038/nn1806. View

17.

Tsuriel S, Fisher A, Wittenmayer N, Dresbach T, Garner C, Ziv N . Exchange and redistribution dynamics of the cytoskeleton of the active zone molecule bassoon. J Neurosci. 2009; 29(2):351-8. PMC: 2768361. DOI: 10.1523/JNEUROSCI.4777-08.2009. View

18.

Hoogenraad C, Milstein A, Ethell I, Henkemeyer M, Sheng M . GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking. Nat Neurosci. 2005; 8(7):906-15. DOI: 10.1038/nn1487. View

19.

Zurner M, Mittelstaedt T, Tom Dieck S, Becker A, Schoch S . Analyses of the spatiotemporal expression and subcellular localization of liprin-α proteins. J Comp Neurol. 2011; 519(15):3019-39. DOI: 10.1002/cne.22664. View

20.

Sudhof T . The presynaptic active zone. Neuron. 2012; 75(1):11-25. PMC: 3743085. DOI: 10.1016/j.neuron.2012.06.012. View