A Trio of Active Zone Proteins Comprised of RIM-BPs, RIMs, and Munc13s Governs Neurotransmitter Release

Brockmann, Marisa M; Zarebidaki, Fereshteh; Camacho, Marcial; Grauel, M. Katharina; Trimbuch, Thorsten; Südhof, Thomas C.; Rosenmund, Christian

doi:10.1016/j.celrep.2020.107960

Cited by 54 publications

(57 citation statements)

References 67 publications

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“…For IHC AZs, this has been suggested to reflect a role of RIM-BP2 in registering new-coming SVs in nanoscale proximity of Ca 2+ channels (Krinner et al, 2017). Recently, a role of RIM-BP in SV priming via interaction with Munc13-1 has been suggested (Brockmann et al, 2020). As priming of SVs in IHCs seems to operate without Munc13 and CAPS priming proteins (Vogl et al, 2015), other protein interactions such as the one with CAST/ELKS (Petzoldt et al, 2020) remain to be studied for a potential involvement in SV replenishment.…”

Section: Introductionmentioning

confidence: 99%

RIM-Binding Proteins Are Required for Normal Sound-Encoding at Afferent Inner Hair Cell Synapses

Krinner

Predoehl

Burfeind

et al. 2021

Front. Mol. Neurosci.

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The afferent synapses between inner hair cells (IHC) and spiral ganglion neurons are specialized to faithfully encode sound with sub-millisecond precision over prolonged periods of time. Here, we studied the role of Rab3 interacting molecule-binding proteins (RIM-BP) 1 and 2 – multidomain proteins of the active zone known to directly interact with RIMs, Bassoon and CaV1.3 – in IHC presynaptic function and hearing. Recordings of auditory brainstem responses and otoacoustic emissions revealed that genetic disruption of RIM-BPs 1 and 2 in mice (RIM-BP1/2–/–) causes a synaptopathic hearing impairment exceeding that found in mice lacking RIM-BP2 (RIM-BP2–/–). Patch-clamp recordings from RIM-BP1/2–/– IHCs indicated a subtle impairment of exocytosis from the readily releasable pool of synaptic vesicles that had not been observed in RIM-BP2–/– IHCs. In contrast, the reduction of Ca2+-influx and sustained exocytosis was similar to that in RIMBP2–/– IHCs. We conclude that both RIM-BPs are required for normal sound encoding at the IHC synapse, whereby RIM-BP2 seems to take the leading role.

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Section: Introductionmentioning

confidence: 99%

RIM-Binding Proteins Are Required for Normal Sound-Encoding at Afferent Inner Hair Cell Synapses

Krinner

Predoehl

Burfeind

et al. 2021

Front. Mol. Neurosci.

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“…What might be the consequence of the variable amounts of Munc13-1 in RSs? Munc13-1 is an evolutionally conserved presynaptic protein that is essential for docking and priming vesicles for release (Augustin et al, 1999;Betz et al, 2001;Brockmann et al, 2020;Imig et al, 2014;Jahn and Fasshauer, 2012;Ma et al, 2011;Varoqueaux et al, 2002) therefore it can be hypothesized that the amount of this molecule might have an effect on the docking site occupancy or the priming state of the vesicles. MPFA only allows the determination of Pv, a probability that depends on the probability of the RS being occupied (Pocc) and on the probability of a docked vesicle being released (Psucc; Neher, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…It is just as unknown whether the normally and superprimed vesicles need different amounts of Munc13-1 or not. It is noteworthy that the priming efficacy of Munc13-1 depends on its interaction with RIM and RIM binding protein (Brockmann et al, 2020) AZs. Maschi and Klyachko (2020) demonstrated that the Pv of centrally located RSs is higher and participate more frequently in multivesicular release (MVR) than those that are located at the periphery of the AZs.…”

Section: Discussionmentioning

confidence: 99%

Diversity of excitatory release sites

Karlócai

Herédi

Benedek

et al. 2021

Preprint

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The molecular mechanisms underlying the diversity of cortical glutamatergic synapses is still only partially understood. Here, we tested the hypothesis that presynaptic active zones (AZs) are constructed from molecularly uniform, independent release sites (RSs), the number of which scales linearly with the AZ size. Paired recordings between hippocampal CA1 pyramidal cells and fast-spiking interneurons followed by quantal analysis demonstrate large variability in the number of RSs (N) at these connections. High resolution molecular analysis of functionally characterized synapses reveals highly variable Munc13-1 content of AZs that possess the same N. Replica immunolabeling also shows a 3-fold variability in the Munc13-1 content of AZs of identical size. Munc13-1 is clustered within the AZs; cluster size and density are also variable. Our results provide evidence for quantitative molecular heterogeneity of RSs and support a model in which the AZ is built up from variable numbers of molecularly heterogeneous, but independent RSs.

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“…This might relate to partial compensation by other candidate linkers of CaV and SV release sites such as long RIM isoforms (Acuna et al, 2016). Recently, two alternative actions of RIM-BPs were indicated based on molecular perturbations studies in hippocampal neurons: i) binding to CaV enabling their tight coupling to SVs or ii) promoting SV priming by interaction with Munc13-1 (Brockmann et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

RIM-Binding Protein 2 organizes Ca²⁺channel topography and regulates release probability and vesicle replenishment at a fast central synapse

Butola

Alvanos

Hintze

et al. 2021

Preprint

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RIM-Binding Protein 2 (RIM-BP2) is a multi-domain protein of the presynaptic active zone (AZ). By binding to Rab-interacting protein (RIM), bassoon and voltage-gated Ca2+ channels (CaV), it is considered to be a central organizer of the topography of CaV and release sites of synaptic vesicles (SVs) at the AZ. Here, we investigated the role of RIM-BP2 at the endbulb of Held synapse of auditory nerve fibers with bushy cells of the cochlear nucleus, a fast relay of the auditory pathway with high release probability. Disruption of RIM-BP2 lowered release probability altering short-term plasticity and reduced evoked excitatory postsynaptic currents (EPSCs). Analysis of SV pool dynamics during high frequency train stimulation indicated a reduction of SVs with high release probability but an overall normal size of the readily releasable SV pool (RRP). The Ca2+-dependent fast component of SV replenishment after RRP depletion was slowed. Augmenting Ca2+ influx by adding extracellular Ca2+ restored release probability but not EPSC amplitude, and uncovered an impairment of SV replenishment during train stimulation. Ultrastructural analysis by super-resolution light and electron microscopy revealed an impaired topography of presynaptic CaV and a reduction of docked and membrane-proximal SVs at the AZ. We conclude that RIM-BP2 organizes the topography of CaV, and promotes SV tethering and docking. This way RIM-BP2 is critical for establishing a high initial release probability as required to reliably signal sound onset information that we found to be degraded in bushy cells of RIM-BP2-deficient mice in vivo.

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A Trio of Active Zone Proteins Comprised of RIM-BPs, RIMs, and Munc13s Governs Neurotransmitter Release

Abstract: Highlights d RBP and RIM are needed for sufficient Ca 2+ influx d RBP2 primes synaptic vesicles via Munc13-1 at small central synapses d RBP2 controls short-term plasticity by vesicle priming or Ca 2+ -channel recruitment

Cited by 54 publications

References 67 publications

RIM-Binding Proteins Are Required for Normal Sound-Encoding at Afferent Inner Hair Cell Synapses

RIM-Binding Proteins Are Required for Normal Sound-Encoding at Afferent Inner Hair Cell Synapses

Diversity of excitatory release sites

RIM-Binding Protein 2 organizes Ca²⁺channel topography and regulates release probability and vesicle replenishment at a fast central synapse

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A Trio of Active Zone Proteins Comprised of RIM-BPs, RIMs, and Munc13s Governs Neurotransmitter Release

Abstract: Highlights d RBP and RIM are needed for sufficient Ca 2+ influx d RBP2 primes synaptic vesicles via Munc13-1 at small central synapses d RBP2 controls short-term plasticity by vesicle priming or Ca 2+ -channel recruitment

Cited by 54 publications

References 67 publications

RIM-Binding Proteins Are Required for Normal Sound-Encoding at Afferent Inner Hair Cell Synapses

RIM-Binding Proteins Are Required for Normal Sound-Encoding at Afferent Inner Hair Cell Synapses

Diversity of excitatory release sites

RIM-Binding Protein 2 organizes Ca2+channel topography and regulates release probability and vesicle replenishment at a fast central synapse

Contact Info

Product

Resources

About

RIM-Binding Protein 2 organizes Ca²⁺channel topography and regulates release probability and vesicle replenishment at a fast central synapse