UNC-2 CaV2 Channel Localization at Presynaptic Active Zones Depends on UNC-10/RIM and SYD-2/Liprin-α in<i>Caenorhabditis elegans</i>

Oh, Kelly H.; Krout, Mia; Richmond, Janet E.; Kim, Hongkyun

doi:10.1523/jneurosci.0076-21.2021

Cited by 30 publications

(31 citation statements)

References 75 publications

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“…To rigorously distinguish these possibilities, further work is required. In a recent publication, RIMB-1 function was assessed with respect to its role in building the synaptic cytomatrix/DP and in anchoring CaV2 channels (Oh et al, 2021). These authors found a contribution of RIMB-1 and a larger effect of UNC-10/RIM mutations on CaV2/UNC-2 abundance at synapses.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the tm5964 allele, which likely retains the N-terminal two thirds of the protein, exhibits a stronger phenotype than the complete deletion of RIMB-1. Also a recent publication reported normal distribution of UNC-2 VGCCs in the rimb-1(ce828) mutant (Oh et al, 2021). Possibly, in the absence of RIMB-1, where also other interactions of its N-terminus with unknown partners are absent, and/or due to compensatory changes, the ce828 animals show near wild type behavior.…”

Section: Rimb-1 Mutants Exhibit Reduced Cholinergic Transmissionmentioning

confidence: 96%

“…Transgenic overexpression of C. elegans GFP::UNC-2 (CaV2) protein can be augmented by overexpressing RIMB-1, and in the rimb-1; unc-10 (RIM) double mutants, as in mice, synaptic abundance of CaV2/UNC-2 channels is reduced (Kushibiki et al, 2019). The molecular interplay of interactions of UNC-10 and RIMB-1 in locating the UNC-2 CaV2 channel has been analyzed in mutants lacking or overexpressing various proteins of the active zone protein scaffold (Oh et al, 2021). However, how RIMB-1 and RIM affect localization of UNC-2 relative to the docked SV is not known in C. elegans, and the synaptic ultrastructure of the rimb-1 mutant is yet to be analyzed.…”

Section: Introductionmentioning

confidence: 99%

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RIM and RIM-binding protein localize synaptic CaV2 channels to differentially regulate transmission in neuronal circuits

Jánosi

et al. 2021

Preprint

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Synapses are intricately organized subcellular compartments in which molecular machines cooperate to ensure spatiotemporally precise transmission of chemical signals. Key components of this machinery are voltage-gated Ca2+-channels (VGCCs), that translate electrical signals into a trigger for fusion of synaptic vesicles (SVs) with the plasma membrane. The VGCCs and the Ca2+ microdomains they generate must be located in the right distance to the primed SV, to elicit transmitter release without delay. Rab3 interacting molecule (RIM) and RIM-binding protein (RIM-BP) were shown in different systems to contribute to the spatial organization of the active zone protein scaffold, and to localize VGCCs next to docked SVs by binding to each other and to the C-terminal region of the Cav2 VGCC α-subunit. We asked how this machinery is organized at the neuromuscular junction (NMJ) of Caenorhabditis elegans, and whether it can differentially regulate transmission in circuits composed of different neuron types. rimb-1 mutants had mild synaptic defects, through loosening the anchoring of the UNC-2 VGCC and delaying the onset of SV fusion, while RIM deletion had much more severe defects. rimb-1 mutants caused increased cholinergic but reduced GABAergic transmission, while overall transmission at the NMJ was reduced, as shown by voltage imaging. The UNC-2 channel could further be untethered by removing its C-terminal PDZ binding motif, and this untethering could be exacerbated by combining the ΔPDZ mutant with the rimb-1 mutation. Similar phenotypes resulted from acute degradation of the UNC-2 β-subunit, indicating that destabilization of the VGCC complex causes the same phenotypes as its untethering.

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Section: Discussionmentioning

confidence: 99%

Section: Rimb-1 Mutants Exhibit Reduced Cholinergic Transmissionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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RIM and RIM-binding protein localize synaptic CaV2 channels to differentially regulate transmission in neuronal circuits

Jánosi

et al. 2021

Preprint

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“…Among the AZ proteins that mediate SV targeting, RIM tethers vesicles to release sites via its interaction with Rab3 (Wang et al, 1997;Betz et al, 2001;Koushika et al, 2001;Schoch et al, 2002;Han et al, 2011). RIM mutants have severely impaired evoked release accompanied by a dramatic reduction in SV docking (Gracheva et al, 2008;Han et al, 2011;Graf et al, 2012;Kushibiki et al, 2019;Oh et al, 2021). Together with the AZ protein SYD-2/Liprin, the C. elegans RIM homolog Unc10 forms filamentous projections that extend from the AZ to capture and tether Rab3 bound SVs at release sites (Gracheva et al, 2008;Stigloher et al, 2011).…”

Section: Snares Rabs and Rab Effectors Contribute To Target Specificity For Membrane Fusionmentioning

confidence: 99%

SNARE Regulatory Proteins in Synaptic Vesicle Fusion and Recycling

Sauvola

Littleton

2021

Front. Mol. Neurosci.

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Membrane fusion is a universal feature of eukaryotic protein trafficking and is mediated by the soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) family. SNARE proteins embedded in opposing membranes spontaneously assemble to drive membrane fusion and cargo exchange in vitro. Evolution has generated a diverse complement of SNARE regulatory proteins (SRPs) that ensure membrane fusion occurs at the right time and place in vivo. While a core set of SNAREs and SRPs are common to all eukaryotic cells, a specialized set of SRPs within neurons confer additional regulation to synaptic vesicle (SV) fusion. Neuronal communication is characterized by precise spatial and temporal control of SNARE dynamics within presynaptic subdomains specialized for neurotransmitter release. Action potential-elicited Ca2+ influx at these release sites triggers zippering of SNAREs embedded in the SV and plasma membrane to drive bilayer fusion and release of neurotransmitters that activate downstream targets. Here we discuss current models for how SRPs regulate SNARE dynamics and presynaptic output, emphasizing invertebrate genetic findings that advanced our understanding of SRP regulation of SV cycling.

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“…Several recent studies took the approach to ablate combinations of active zone protein families to analyze active zone assembly and function by eliminating redundant components (Acuna et al, 2016; Brockmann et al, 2020; Kushibiki et al, 2019; Oh et al, 2021; Tan et al, 2022; Wang et al, 2016; Zarebidaki et al, 2020). We simultaneously deleted RIM1, RIM2, ELKS1 and ELKS2, which resulted in a loss of RIM, ELKS, and Munc13, and in a strong decrease of Bassoon, Piccolo, and RIM-BP levels at active zones (Tan et al, 2022; Wang et al, 2016; Wong et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Munc13 supports vesicle fusogenicity after disrupting active zone scaffolds and synaptic vesicle docking

Tan

Nola

Qiao

et al. 2022

Preprint

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Active zones consist of protein scaffolds that are tightly attached to the presynaptic plasma membrane. They dock and prime synaptic vesicles, couple them to Ca2+ entry, and target neurotransmitter release to postsynaptic receptor domains. Simultaneous RIM+ELKS ablation disrupts these scaffolds, abolishes vesicle docking and removes active zone-targeted Munc13, but some vesicles remain releasable. This enduring vesicular fusogenicity may be Munc13-independent or be mediated by non-active zone-anchored Munc13. We tested its Munc13-dependence by ablating Munc13-1 and Munc13-2 on top of RIM+ELKS in cultured hippocampal neurons. The hextuple knockout synapses lacked docked vesicles, but other ultrastructural features were near-normal despite the strong genetic manipulation. Removing Munc13 in addition to RIM+ELKS further impaired action potential-evoked release by decreasing the remaining pool of releasable vesicles. We conclude that Munc13 can support some fusogenicity without RIM and ELKS, and that presynaptic recruitment of Munc13, even without active zone-anchoring, suffices to generate some fusion-competent vesicles.

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UNC-2 CaV2 Channel Localization at Presynaptic Active Zones Depends on UNC-10/RIM and SYD-2/Liprin-α inCaenorhabditis elegans

Cited by 30 publications

References 75 publications

RIM and RIM-binding protein localize synaptic CaV2 channels to differentially regulate transmission in neuronal circuits

RIM and RIM-binding protein localize synaptic CaV2 channels to differentially regulate transmission in neuronal circuits

SNARE Regulatory Proteins in Synaptic Vesicle Fusion and Recycling

Munc13 supports vesicle fusogenicity after disrupting active zone scaffolds and synaptic vesicle docking

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