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Molecular Neurophysiology

 

 

Elife. 2018 Jul 25;7. pii: e38981. doi: 10.7554/eLife.38981. [Epub ahead of print]

A mechanism for exocytotic arrest by the Complexin C-terminus.

ComplexinII (CpxII) inhibits non-synchronized vesicle fusion, but the underlying mechanisms have remained unclear. Here, we provide evidence that the far C-terminal domain (CTD) of CpxII interferes with SNARE assembly, thereby arresting tonic exocytosis. Acute infusion of a CTD-derived peptide into mouse chromaffin cells enhances synchronous release by diminishing premature vesicle fusion like full-length CpxII, indicating a direct, inhibitory function of the CTD that sets the magnitude of the primed vesicle pool. We describe a high degree of structural similarity between the CpxII CTD and the SNAP25-SN1 domain (C-terminal half) and show that the CTD peptide lowers the rate of SDS-resistant SNARE complex formation in vitro. Moreover, corresponding CpxII:SNAP25 chimeras do restore complexin's function and even 'superclamp' tonic secretion. Collectively, these results support a so far unrecognized clamping mechanism wherein the CpxII C-terminus hinders spontaneous SNARE complex assembly, enabling the build-up of a release-ready pool of vesicles for synchronized Ca2+-triggered exocytosis.

KEYWORDS:

mouse; neuroscience

PMID:30044227
DOI:10.7554/eLife.38981

Nat Neurosci. 2017 Sep 25. doi: 10.1038/nn.4647. [Epub ahead of print]

Astrocytes control synaptic strength by two distinct v-SNARE-dependent release pathways.
Schwarz Y.(1), Zhao N.(2), Kirchhoff F.(2), Bruns D(1).

 


Author information

1 Molecular Neurophysiology, Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany.
2 Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany.


Abstract
Communication between glia cells and neurons is crucial for brain functions, but the molecular mechanisms and functional consequences of gliotransmission remain enigmatic. Here we report that astrocytes express synaptobrevin II and cellubrevin as functionally non-overlapping vesicular SNARE proteins on glutamatergic vesicles and neuropeptide Y-containing large dense-core vesicles, respectively. Using individual null-mutants for Vamp2 (synaptobrevin II) and Vamp3 (cellubrevin), as well as the corresponding compound null-mutant for genes encoding both v-SNARE proteins, we delineate previously unrecognized individual v-SNARE dependencies of astrocytic release processes and their functional impact on neuronal signaling. Specifically, we show that astroglial cellubrevin-dependent neuropeptide Y secretion diminishes synaptic signaling, while synaptobrevin II-dependent glutamate release from astrocytes enhances synaptic signaling. Our experiments thereby uncover the molecular mechanisms of two distinct v-SNARE-dependent astrocytic release pathways that oppositely control synaptic strength at presynaptic sites, elucidating new avenues of communication between astrocytes and neurons.
PMID:28945220
DOI:10.1038/nn.4647

EMBO J. 2017 Sep 15;36(18):2770-2789. doi: 10.15252/embj.201696369. Epub 2017 Aug 8.

Heteromeric channels formed by TRPC1, TRPC4 and TRPC5 define hippocampal synaptic transmission and working memory.

Bröker-Lai J1, Kollewe A2, Schindeldecker B3, Pohle J1,4, Nguyen Chi V5, Mathar I1, Guzman R3, Schwarz Y3, Lai A1, Weißgerber P6, Schwegler H7, Dietrich A8, Both M5, Sprengel R9, Draguhn A5, Köhr G4, Fakler B2,10, Flockerzi V6, Bruns D3, Freichel M11.

Author information
Abstract

Canonical transient receptor potential (TRPC) channels influence various neuronal functions. Using quantitative high-resolution mass spectrometry, we demonstrate that TRPC1, TRPC4, and TRPC5 assemble into heteromultimers with each other, but not with other TRP family members in the mouse brain and hippocampus. In hippocampal neurons from Trpc1/Trpc4/Trpc5-triple-knockout (Trpc1/4/5-/-) mice, lacking any TRPC1-, TRPC4-, or TRPC5-containing channels, action potential-triggered excitatory postsynaptic currents (EPSCs) were significantly reduced, whereas frequency, amplitude, and kinetics of quantal miniature EPSC signaling remained unchanged. Likewise, evoked postsynaptic responses in hippocampal slice recordings and transient potentiation after tetanic stimulation were decreased. In vivo, Trpc1/4/5-/- mice displayed impaired cross-frequency coupling in hippocampal networks and deficits in spatial working memory, while spatial reference memory was unaltered. Trpc1/4/5-/- animals also exhibited deficiencies in adapting to a new challenge in a relearning task. Our results indicate the contribution of heteromultimeric channels from TRPC1, TRPC4, and TRPC5 subunits to the regulation of mechanisms underlying spatial working memory and flexible relearning by facilitating proper synaptic transmission in hippocampal neurons.
© 2017 The Authors.KEYWORDS:
TRPC1/C4/C5 heteromeric assembly; cross‐frequency coupling; hippocampal synaptic transmission; relearning; spatial working memory
PMID:28790178
DOI:10.15252/embj.201696369 

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