Molecular Neurophysiology



Elife. 2020 May 11;9.

Synergistic actions of v-SNARE transmembrane domains and membrane-curvature modifying lipids in neurotransmitter release

Dhara M1, Mantero Martinez M1, Makke M1, Schwarz Y1, Mohrmann R2, Bruns D1.

1 Institute for Physiology, Center of Integrative Physiology and Molecular Medicine, University of Saarland, Homburg, Germany.

2 Institute of Physiology, Otto-von-Guericke University, Magdeburg, Germany.


Vesicle fusion is mediated by assembly of SNARE proteins between opposing membranes. While previous work suggested an active role of SNARE transmembrane domains (TMDs) in promoting membrane merger (Dhara et al., 2016), the underlying mechanism remained elusive. Here, we show that naturally-occurring v-SNARE TMD variants differentially regulate fusion pore dynamics in mouse chromaffin cells, indicating TMD flexibility as a mechanistic determinant that facilitates transmitter release from differentially-sized vesicles. Membrane curvature-promoting phospholipids like lysophosphatidylcholine or oleic acid profoundly alter pore expansion and fully rescue the decelerated fusion kinetics of TMD-rigidifying VAMP2 mutants. Thus, v-SNARE TMDs and phospholipids cooperate in supporting membrane curvature at the fusion pore neck. Oppositely, slowing of pore kinetics by the SNARE-regulator complexin-2 withstands the curvature-driven speeding of fusion, indicating that pore evolution is tightly coupled to progressive SNARE complex formation. Collectively, TMD-mediated support of membrane curvature and SNARE force-generated membrane bending promote fusion pore formation and expansion.


 to study



(Homburg/Saar) Germany


Ph.D. positions are available to elucidate the molecular mechanisms that mediate neuronal exocytosis. Our goal is to define the molecular events that couple Ca2+ signaling to the release of neurotransmitter. We  are  addressing  this  problem  with  state-of-the-art  molecular  (knock-out  mice),biochemical, electrophysiological  and  fluorescence  microscopy  techniques  (e.g.  carbon fiber  amperometry, membrane capacitance measurements, Ca2+-imaging, SIM and STED microscopy). The work is directly supported by technical personnel and applicants are given the opportunity to extend their research interest internationally through project–oriented collaborations with groups in the USA. Applicants with a physical, biochemical or biological background are encouraged to apply.

Please send your curriculum vitae and a brief statement of research interest to: Prof. Dr. Dieter Bruns, Dept. of Physiology, Center of Integrated Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Building 48, Germany, Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Exemplary publications:

Schwarz Y, Oleinikov K, Schindeldecker B, Wyatt A, Weißgerber P, Flockerzi V, Boehm U, Freichel M, Bruns D (2019). TRPC channels regulate Ca2+-signaling and short-term plasticity of fast glutamatergic synapses. PLOS Biol., doi: 10.1371/journal.pbio.3000445

Makke M, Mantero Martinez M, Gaya S, Schwarz Y, Frisch W, Silva-Bermudez L, Jung M2, Mohrmann R, Dhara M, Bruns D (2018). A mechanism for exocytotic arrest by the Complexin C-terminus. Elife. doi: 10.7554/eLife.38981.

Dhara M, Mohrmann R, Bruns D (2018). v-SNARE function in chromaffin cells. Pflugers Arch., 470:169-180.

Schwarz Y, Zhao N, Kirchhoff F, Bruns D. (2017). Astrocytes control synaptic strength by two distinct v-SNARE-dependent release pathways. Nat Neurosci.20:1529-1539.



PLoS Biol. 2019 Sep 19;17(9)

TRPC channels regulate Ca2+-signaling and short-term plasticity of fast glutamatergic synapses.

Schwarz Y, Oleinikov K, Schindeldecker B, Wyatt A, Weißgerber P, Flockerzi V, Boehm U, Freichel M, Bruns D.

Transient receptor potential (TRP) proteins form Ca2+-permeable, nonselective cation channels, but their role in neuronal Ca2+ homeostasis is elusive. In the present paper, we show that TRPC channels potently regulate synaptic plasticity by changing the presynaptic Ca2+-homeostasis of hippocampal neurons. Specifically, loss of TRPC1/C4/C5 channels decreases basal-evoked secretion, decreases the pool size of readily releasable vesicles, and accelerates synaptic depression during high-frequency stimulation (HFS). In contrast, primary TRPC5 channel-expressing neurons, identified by a novel TRPC5-τ-green fluorescent protein (τGFP) knockin mouse line, show strong short-term enhancement (STE) of synaptic signaling during HFS, indicating a key role of TRPC5 in short-term plasticity. Lentiviral expression of either TRPC1 or TRPC5 turns classic synaptic depression of wild-type neurons into STE, demonstrating that TRPCs are instrumental in regulating synaptic plasticity. Presynaptic Ca2+ imaging shows that TRPC activity strongly boosts synaptic Ca2+ dynamics, showing that TRPC channels provide an additional presynaptic Ca2+ entry pathway, which efficiently regulates synaptic strength and plasticity.


Elife. 2018 Jul 25;7.

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.


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