A Presynaptic Role for the Cytomatrix Protein GIT in Synaptic Vesicle Recycling

Podufall, Jasmin; Tian, Rui; Knoche, Elena; Puchkov, Dmytro; Walter, Alexander; Rosa, Stefanie; Quentin, Christine; Vukoja, Anela; Jung, Nadja; Lampe, André; Wichmann, Carolin; Böhme, Mathias A.; Depner, Harald; Zhang, Yong Q.; Schmoranzer, Jan; Sigrist, Stephan J.; Haucke, Volker

doi:10.1016/j.celrep.2014.04.051

Cited by 37 publications

(43 citation statements)

References 37 publications

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“…In coimmunoprecipitations from P2 fractions of mouse brains, RIM-BP2 coprecipitated with RIM and Munc13-1, but not with the Arf GTPase-activating protein GIT, a binding partner of Piccolo (9) and of endocytotic proteins such as Dynamin1 (Fig. S1E) and Stonin 2 (10). Together, these results indicate that RIM-BP2 is part of the presynaptic AZ scaffold and forms a complex with the priming factors RIM and Munc13-1.…”

Section: Resultssupporting

confidence: 53%

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

Grauel

Maglione

Reddy-Alla

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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102

178

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The tight spatial coupling of synaptic vesicles and voltage-gated Ca 2+ channels (Ca V s) ensures efficient action potential-triggered neurotransmitter release from presynaptic active zones (AZs). Rab-interacting molecule-binding proteins (RIM-BPs) interact with Ca 2+ channels and via RIM with other components of the release machinery. Although human RIM-BPs have been implicated in autism spectrum disorders, little is known about the role of mammalian RIM-BPs in synaptic transmission. We investigated RIM-BP2-deficient murine hippocampal neurons in cultures and slices. Short-term facilitation is significantly enhanced in both model systems. Detailed analysis in culture revealed a reduction in initial release probability, which presumably underlies the increased shortterm facilitation. Superresolution microscopy revealed an impairment in Ca V 2.1 clustering at AZs, which likely alters Ca 2+ nanodomains at release sites and thereby affects release probability. Additional deletion of RIM-BP1 does not exacerbate the phenotype, indicating that RIM-BP2 is the dominating RIM-BP isoform at these synapses.RIM-BP2 | calcium channel coupling | release probability | short-term plasticity | active zone structure A t the presynapse, coupling between action potentials (APs) and synaptic vesicle fusion is exquisitely precise, ensuring high temporal fidelity of neuron-to-neuron signaling in the nervous system. Two properties are thought to be responsible for this remarkable precision: a highly efficient release apparatus that transduces Ca 2+ signals into vesicle fusion and a tightly organized active zone (AZ), where the release apparatus and voltage-gated Ca 2+ channels (Ca V s) are spatially coupled. Rab-interacting molecules (RIM) are thought to contribute to both properties, because loss of RIM impairs vesicle priming (1) and Ca V localization at the AZ (2). RIM-binding proteins (RIM-BPs) directly interact with RIM (3), the pore-forming subunits of Ca V 1 and Ca V 2 channels (2, 4, 5), and Bassoon (5), and have therefore been suggested to play a role in presynaptic Ca V localization. The Drosophila homolog of RIM-binding proteins (DRBP) is indeed crucial for neurotransmitter release at the AZ of neuromuscular junctions (NMJs) because loss of DRBP reduces Ca V abundance and impairs the integrity of the AZ scaffold (6). DRBP-deficient flies show severe impairment of neurotransmitter release along with increased short-term facilitation (6, 7).Recently, Acuna et al. (8) published a report on the combined loss of RIM-BP1 and RIM-BP2 in mouse synapses. The authors report that although RIM-BPs are not essential for synaptic transmission, AP-triggered neurotransmitter release is more variable and the sensitivity to the Ca 2+ chelator EGTA is increased at the Calyx of Held, suggesting a larger coupling distance of Ca V and the release machinery.In the present study, we further investigated the consequences of constitutive deletion of RIM-BP2 on the structure and function of mouse hippocampal synapses. We show that loss of RIM-BP2 lead...

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Section: Resultssupporting

confidence: 53%

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

Grauel

Maglione

Reddy-Alla

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

102

178

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“…Moreover, genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the genes encoding for the AP180 paralog CALM, dynamin 2, and amphiphysin 1 in familial and sporadic cases of Alzheimer's disease (Aidaralieva et al, 2008;Harold et al, 2009;Seshadri et al, 2010). Finally, GIT1 (termed dGIT in Drosophila), an AZ-associated scaffold with GTPase activating protein activity toward Arf6, associates with stonin 2/stoned B and regulates SV recycling (Podufall et al, 2014). Human mutations in GIT1, which is also found postsynaptically, are associated with attention deficit hyperactivity disorder (ADHD) and cause ADHD-like phenotypes in GIT1 mutant mice (Won et al, 2011).…”

Section: Perspectivesmentioning

confidence: 99%

Molecular Mechanisms of Presynaptic Membrane Retrieval and Synaptic Vesicle Reformation

Kononenko

Haucke

2015

Neuron

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185

194

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The function of the nervous system depends on the exocytotic release of neurotransmitter from synaptic vesicles (SVs). To sustain neurotransmission, SV membranes need to be retrieved, and SVs have to be reformed locally within presynaptic nerve terminals. In spite of more than 40 years of research, the mechanisms underlying presynaptic membrane retrieval and SV recycling remain controversial. Here, we review the current state of knowledge in the field, focusing on the molecular mechanism involved in presynaptic membrane retrieval and SV reformation. We discuss the challenges associated with studying these pathways and present perspectives for future research.

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“…The release of neurotransmitter vesicles is restricted to the presynaptic active zone through a macromolecular complex called the presynaptic cytoplasmic matrix or cytomatrix (Gundelfinger and Fejtova, 2012). GIT1, in complex with β-PIX and paxillin, binds the cytomatrix proteins piccolo and stonin-2 (Podufall et al, 2014) to regulate localized neurotransmitter vesicle release and reuptake. In Drosophila, dGIT interacts with stoned B at the periphery of the synaptic active zone, and dgit mutant flies have defective synaptic vesicle recycling (Podufall et al, 2014).…”

Section: Functions In the Nervous Systemmentioning

confidence: 99%

“…GIT and PIX each bind partner proteins that localize the complex to specific cellular locations. These proteins include the GIT partners paxillin (to focal adhesions; Turner et al, 1999), piccolo and stonin-2 (to presynaptic active zones in neurons; Kim et al, 2003;Podufall et al, 2014) and liprin-α (to postsynaptic membranes; Ko et al, 2003), as well as the β-PIX PDZ partners scribble (to epithelial cell-cell contacts and synapses; Audebert et al, 2004;Richier et al, 2010) and shank (to postsynaptic membranes; Park et al, 2003).…”

Section: Git Proteinsmentioning

confidence: 99%

“…GIT1, in complex with β-PIX and paxillin, binds the cytomatrix proteins piccolo and stonin-2 (Podufall et al, 2014) to regulate localized neurotransmitter vesicle release and reuptake. In Drosophila, dGIT interacts with stoned B at the periphery of the synaptic active zone, and dgit mutant flies have defective synaptic vesicle recycling (Podufall et al, 2014). In the mouse calyx of Held synapse, presynaptic GIT1, or GIT1 together with GIT2, constrains the probability of synaptic vesicle release without altering the readily releasable pool of vesicles; however, GIT2 alone has no significant effect (Montesinos et al, 2015).…”

Section: Functions In the Nervous Systemmentioning

confidence: 99%

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Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

Weiyuan

Premont

2016

Journal of Cell Science

100

130

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The GIT proteins, GIT1 and GIT2, are GTPase-activating proteins (inactivators) for the ADP-ribosylation factor (Arf ) small GTP-binding proteins, and function to limit the activity of Arf proteins. The PIX proteins, α-PIX and β-PIX (also known as ARHGEF6 and ARHGEF7, respectively), are guanine nucleotide exchange factors (activators) for the Rho family small GTP-binding protein family members Rac1 and Cdc42. Through their multi-domain structures, GIT and PIX proteins can also function as signaling scaffolds by binding to numerous protein partners. Importantly, the constitutive association of GIT and PIX proteins into oligomeric GIT-PIX complexes allows these two proteins to function together as subunits of a larger structure that coordinates two distinct small GTP-binding protein pathways and serves as multivalent scaffold for the partners of both constituent subunits. Studies have revealed the involvement of GIT and PIX proteins, and of the GIT-PIX complex, in numerous fundamental cellular processes through a wide variety of mechanisms, pathways and signaling partners. In this Commentary, we discuss recent findings in key physiological systems that exemplify current understanding of the function of this important regulatory complex. Further, we draw attention to gaps in crucial information that remain to be filled to allow a better understanding of the many roles of the GIT-PIX complex in health and disease.

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A Presynaptic Role for the Cytomatrix Protein GIT in Synaptic Vesicle Recycling

Cited by 37 publications

References 37 publications

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

Molecular Mechanisms of Presynaptic Membrane Retrieval and Synaptic Vesicle Reformation

Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

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