RIM-Binding Protein Links Synaptic Homeostasis to the Stabilization and Replenishment of High Release Probability Vesicles

Müller, Martin; Genç, Özgür; Davis, Graeme W.

doi:10.1016/j.neuron.2015.06.010

Cited by 19 publications

(50 citation statements)

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“…The BLOC‐1 subunit dysbindin was identified as a central mediator of the presynaptic homeostatic plasticity that follows postsynaptic glutamatergic receptors inhibition (Dickman & Davis, ), functioning in concert with snapin in flies (Dickman et al , ). Interestingly, it was recently proposed that this homeostatic phenomenon involves a tightening of SV coupling to Ca 2+ influx (Müller et al , ), and both Rab3 and dysbindin have been suggested to influence SV positional priming during such presynaptic homeostasis (Müller et al , ). Thus, our data and reports from others consistently indicate that BLOC‐1‐dependent processes contribute to the Ca 2+ sensitivity of SV exocytosis, by regulating the SV‐Ca 2+ channels coupling.…”

Section: Discussionmentioning

confidence: 99%

Regulation of synaptic activity by snapin‐mediated endolysosomal transport and sorting

Giovanni

Sheng

2015

The EMBO Journal

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Recycling synaptic vesicles (SVs) transit through early endosomal sorting stations, which raises a fundamental question: are SVs sorted toward endolysosomal pathways? Here, we used snapin mutants as tools to assess how endolysosomal sorting and trafficking impact presynaptic activity in wild-type and snapin À/À neurons. Snapin acts as a dynein adaptor that mediates the retrograde transport of late endosomes (LEs) and interacts with dysbindin, a subunit of the endosomal sorting complex BLOC-1. Expressing dynein-binding defective snapin mutants induced SV accumulation at presynaptic terminals, mimicking the snapin À/À phenotype. Conversely, over-expressing snapin reduced SV pool size by enhancing SV trafficking to the endolysosomal pathway. Using a SV-targeted Ca2+ sensor, we demonstrate that snapindysbindin interaction regulates SV positional priming through BLOC-1/AP-3-dependent sorting. Our study reveals a bipartite regulation of presynaptic activity by endolysosomal trafficking and sorting: LE transport regulates SV pool size, and BLOC-1/AP-3-dependent sorting fine-tunes the Ca 2+ sensitivity of SV release.Therefore, our study provides new mechanistic insights into the maintenance and regulation of SV pool size and synchronized SV fusion through snapin-mediated LE trafficking and endosomal sorting.

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Section: Discussionmentioning

confidence: 99%

Regulation of synaptic activity by snapin‐mediated endolysosomal transport and sorting

Giovanni

Sheng

2015

The EMBO Journal

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“…This finding suggested that RIMs tether Ca 2+ channels both by directly binding to Ca 2+ channels via their PDZ domains and by indirectly recruiting Ca 2+ channels via RIM-BPs. Consistent with this hypothesis, deletion of RIM-BP in Drosophila neuromuscular synapses causes severe structural and functional impairments (Liu et al, 2011;Mü ller et al, 2012Mü ller et al, , 2015. However, no characterization of RIM-BP function in mammalian synapses is available.…”

Section: Introductionmentioning

confidence: 89%

RIM-BPs Mediate Tight Coupling of Action Potentials to Ca 2+ -Triggered Neurotransmitter Release

Acuña

Liu

Gonzalez-Suarez

et al. 2015

Neuron

104

218

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Ultrafast neurotransmitter release requires tight colocalization of voltage-gated Ca(2+) channels with primed, release-ready synaptic vesicles at the presynaptic active zone. RIM-binding proteins (RIM-BPs) are multidomain active zone proteins that bind to RIMs and to Ca(2+) channels. In Drosophila, deletion of RIM-BPs dramatically reduces neurotransmitter release, but little is known about RIM-BP function in mammalian synapses. Here, we generated double conditional knockout mice for RIM-BP1 and RIM-BP2, and analyzed RIM-BP-deficient synapses in cultured hippocampal neurons and the calyx of Held. Surprisingly, we find that in murine synapses, RIM-BPs are not essential for neurotransmitter release as such, but are selectively required for high-fidelity coupling of action potential-induced Ca(2+) influx to Ca(2+)-stimulated synaptic vesicle exocytosis. Deletion of RIM-BPs decelerated action-potential-triggered neurotransmitter release and rendered it unreliable, thereby impairing the fidelity of synaptic transmission. Thus, RIM-BPs ensure optimal organization of the machinery for fast release in mammalian synapses without being a central component of the machinery itself.

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“…brp is essential for active zone development, organization, and close apposition and clustering of calcium channels and vesicles (KITTEL et al 2006;FOUQUET et al 2009;MATKOVIC et al 2013). Calcium channels are also localized by the actions of the Rab3 (GRAF et al 2009) and Rab3interacting molecule (RIM) (LIU et al 2011;GRAF et al 2012), which together with RIMbinding protein also couple to the vesicle pool (MULLER et al 2011;MULLER et al 2012;MULLER et al 2015). These effects are reminiscent of similar effects from mammalian synapses (HAN et al 2011;GANDINI and FELIX 2012;KAESER et al 2012;KIYONAKA et al 2012;HAN et al 2015).…”

Section: Cacophony (Cac)mentioning

confidence: 99%

“…However, it is also worth noting that the two mechanisms are not entirely separate (MULLER et al 2015). It has been put forward that changes to the calcium transient effectively increase the size of the calcium domain, thereby recruiting more distant or release-resistant vesicles for exocytosis in both flies and mammals (THANAWALA and REGEHR 2013;DAVIS and MÜLLER 2015).…”

Section: Glutamate Receptor Loss and Homeostasis At The Drosophila Nmjmentioning

confidence: 99%

“…Removal of endostatin is known to affect baseline neurotransmission, the amplitude of the presynaptic calcium transient, and blocks homeostatic compensation. Similarly, Rab3 interacting molecule (RIM) and RIM-binding protein are necessary for calcium channel accumulation at the active zone, calcium transient potentiation, and both also block homeostatic potentiation (GRAF et al 2009;GRAF et al 2012;MULLER et al 2012;MULLER et al 2015). Likewise, bruchpilot (brp) promotes calcium channel accumulation at the active zone (KITTEL et al 2006).…”

Section: Calcium-related Pathwaysmentioning

confidence: 99%

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Dual roles for an intracellular calcium-signaling pathway in regulating synaptic homeostasis and neuronal excitability

Brusich¹

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vi also what I often needed most. Mom, thanks for always instilling the belief that I could do anything. Nathan, thanks for being equal parts counselor and brother. I could not have gotten through some of the more difficult emotional times without you. Steven, thanks for your humorous texts from home, keeping in touch, and your confidence to stick with it. Lastly, thank you to Whitney. At times it seemed the only good thing to come from lab was having met you. Thank you for listening as I talked through anxieties, frustrations, and career meanderings. Your support never faltered. Thanks also for the joys of cooking dinner together, farmers market Saturdays, walks, quiet study nights, Frisbee (yes, Frisbee), bad movies, and just being silly. I appreciated every moment with you and relied on you to make it to this point. I only hope I can be as supportive of you as you have been of me.

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RIM-Binding Protein Links Synaptic Homeostasis to the Stabilization and Replenishment of High Release Probability Vesicles

Cited by 19 publications

References 0 publications

Regulation of synaptic activity by snapin‐mediated endolysosomal transport and sorting

Regulation of synaptic activity by snapin‐mediated endolysosomal transport and sorting

RIM-BPs Mediate Tight Coupling of Action Potentials to Ca 2+ -Triggered Neurotransmitter Release

Dual roles for an intracellular calcium-signaling pathway in regulating synaptic homeostasis and neuronal excitability

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