Calcium-sensitive Activity and Conformation of Caenorhabditis elegans Gelsolin-like Protein 1 Are Altered by Mutations in the First Gelsolin-like Domain

Liu, Zhongmei; Kanzawa, Nobuyuki; Ono, Shoichiro

doi:10.1074/jbc.m111.237404

Cited by 8 publications

(9 citation statements)

References 28 publications

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“…Because synaptic removal is activated during a discrete developmental period, a specific signal is likely required to trigger this pathway. Based on our finding that calcium signaling and UNC-8 function together to promote GABA synapse elimination and previous work that detected roles for calcium in caspase activation and gelsolin function ( Pinan-Lucarre et al, 2012 ; Liu et al, 2011 ), we considered the possibility that these components function in a common pathway and that calcium activates the overall mechanism. To test this idea, we first asked if the cell death gene ced-4 is required for GABA synapse removal in unc-55 mutants in which both DD and VD neurons remodel.…”

Section: Resultsmentioning

confidence: 99%

“…Recent work has shown that functional synaptic components can also be removed by the canonical apoptotic protease, caspase-3 ( Ertürk et al, 2014 ; Wang et al, 2014 ). In C. elegans , the cell death pathway component CED-3/caspase-3 and its upstream regulator CED-4/Apaf1 promote synaptic disassembly by activating the F-actin severing protein gelsolin; the calcium sensitivity of this pathway points to a potential role for neuronal activity in synaptic remodeling ( Pinan-Lucarre et al, 2012 ; Meng et al, 2015 ; Liu et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

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The DEG/ENaC cation channel protein UNC-8 drives activity-dependent synapse removal in remodeling GABAergic neurons

Petersen

Manning

Matthewman

et al. 2016

eLife

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Genetic programming and neural activity drive synaptic remodeling in developing neural circuits, but the molecular components that link these pathways are poorly understood. Here we show that the C. elegans Degenerin/Epithelial Sodium Channel (DEG/ENaC) protein, UNC-8, is transcriptionally controlled to function as a trigger in an activity-dependent mechanism that removes synapses in remodeling GABAergic neurons. UNC-8 cation channel activity promotes disassembly of presynaptic domains in DD type GABA neurons, but not in VD class GABA neurons where unc-8 expression is blocked by the COUP/TF transcription factor, UNC-55. We propose that the depolarizing effect of UNC-8-dependent sodium import elevates intracellular calcium in a positive feedback loop involving the voltage-gated calcium channel UNC-2 and the calcium-activated phosphatase TAX-6/calcineurin to initiate a caspase-dependent mechanism that disassembles the presynaptic apparatus. Thus, UNC-8 serves as a link between genetic and activity-dependent pathways that function together to promote the elimination of GABA synapses in remodeling neurons.DOI: http://dx.doi.org/10.7554/eLife.14599.001

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The DEG/ENaC cation channel protein UNC-8 drives activity-dependent synapse removal in remodeling GABAergic neurons

Petersen

Manning

Matthewman

et al. 2016

eLife

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“…In axon regeneration, elevation of calcium concentration upon injury can activate CED-4 to promote axonal regrowth (Pinan-Lucarre et al, 2012). The second gelsolin domain of GSNL-1 can change its conformation upon binding with calcium to regulate its F-actin severing ability (Liu et al, 2011). These findings suggest that change in local calcium concentration either by neuronal activity or ER/mitochondrial release may modulate the strength of the CED-GSNL-1 pathway in synapse elimination.…”

Section: Discussionmentioning

confidence: 99%

The Cell Death Pathway Regulates Synapse Elimination through Cleavage of Gelsolin in Caenorhabditis elegans Neurons

et al. 2015

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Summary Synapse elimination occurs in development, plasticity and disease conditions. Although the importance of synapse elimination has been documented in many studies, the molecular mechanisms underlying this process remain to be understood. Here, using the development of C. elegans RME neurons as a model, we have uncovered the function of the apoptosis pathway in synapse elimination. We find that the conserved apoptotic cell death (CED) pathway and axonal mitochondria are required for elimination of transiently formed clusters of presynaptic components in RME neurons. The function of the CED pathway needs the activation of the actin filament severing protein, GSNL-1. Furthermore, we show that caspase CED-3 cleaves GSNL-1 at a conserved C-terminal region, and that the cleaved active form of GSNL-1 promotes its actin severing ability. Our data suggest that activation of the cell death pathway contributes to selective elimination of synapses through disassembly of actin filament network.

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“…Microscopic observation of actin filament severing was performed as described previously [ 20 , 36 ]. Preformed F-actin (5 μM) was incubated with 100 or 200 nM ABP29 or ABP135 G1-G3 in the presence of various concentrations of free Ca 2+ at room temperature for 30 min, and the reaction mixtures were labeled with Alexa 488-phalloidin (Molecular Probes Invitrogen), as previously described [ 6 ].…”

Section: Methodsmentioning

confidence: 99%

Gelsolin-Like Domain 3 Plays Vital Roles in Regulating the Activities of the Lily Villin/Gelsolin/Fragmin Superfamily

et al. 2015

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The villin/gelsolin/fragmin superfamily is a major group of Ca2+-dependent actin-binding proteins (ABPs) involved in various cellular processes. Members of this superfamily typically possess three or six tandem gelsolin-like (G) domains, and each domain plays a distinct role in actin filament dynamics. Although the activities of most G domains have been characterized, the biochemical function of the G3 domain remains poorly understood. In this study, we carefully compared the detailed biochemical activities of ABP29 (a new member of this family that contains the G1-G2 domains of lily ABP135) and ABP135G1-G3 (which contains the G1-G3 domains of lily ABP135). In the presence of high Ca2+ levels in vitro (200 and 10 μM), ABP135G1-G3 exhibited greater actin severing and/or depolymerization and nucleating activities than ABP29, and these proteins had similar actin capping activities. However, in the presence of low levels of Ca2+ (41 nM), ABP135G1-G3 had a weaker capping activity than ABP29. In addition, ABP29 inhibited F-actin depolymerization, as shown by dilution-mediated depolymerization assay, differing from the typical superfamily proteins. In contrast, ABP135G1-G3 accelerated F-actin depolymerization. All of these results demonstrate that the G3 domain plays specific roles in regulating the activities of the lily villin/gelsolin/fragmin superfamily proteins.

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Calcium-sensitive Activity and Conformation of Caenorhabditis elegans Gelsolin-like Protein 1 Are Altered by Mutations in the First Gelsolin-like Domain

Cited by 8 publications

References 28 publications

The DEG/ENaC cation channel protein UNC-8 drives activity-dependent synapse removal in remodeling GABAergic neurons

The DEG/ENaC cation channel protein UNC-8 drives activity-dependent synapse removal in remodeling GABAergic neurons

The Cell Death Pathway Regulates Synapse Elimination through Cleavage of Gelsolin in Caenorhabditis elegans Neurons

Gelsolin-Like Domain 3 Plays Vital Roles in Regulating the Activities of the Lily Villin/Gelsolin/Fragmin Superfamily

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