Structural Insights into the Synaptic Vesicle V-ATPase-Synaptophysin Complex and Its Role in Neurotransmitter Release

Core Concepts

The synaptic vesicle V-ATPase and synaptophysin form a well-defined complex that is crucial for the biogenesis and function of synaptic vesicles, with implications for neurotransmitter release and seizure susceptibility.

Abstract

The content provides insights into the structural and functional relationship between the synaptic vesicle V-ATPase and the protein synaptophysin. Key highlights:

1. The V-ATPase is an ATP-dependent proton pump that establishes the protein gradient across the synaptic vesicle, driving the uptake of neurotransmitters.
2. Synaptophysin and its paralogs (synaptoporin and synaptogyrin) are abundant synaptic vesicle proteins with unclear functions.
3. Using cryo-electron tomography and microscopy, the authors discovered a well-defined interface between the V-ATPase and synaptophysin in functional synaptic vesicles isolated from mouse brains.
4. While the conformation of the V-ATPase is largely unaffected by the interaction with synaptophysin, the presence of synaptophysin significantly impacts the copy number of V-ATPases on synaptic vesicles.
5. Synaptophysin knockout mice exhibit severe seizure susceptibility, suggesting that the V-ATPase-synaptophysin complex is crucial for the proper biogenesis and function of synaptic vesicles, with implications for neurotransmitter release.
6. The study provides structural and functional insights into the role of the V-ATPase-synaptophysin complex in the biogenesis and regulation of synaptic vesicles, which is important for understanding neurotransmission and neurological disorders.

Stats

Synaptic vesicles have a precisely defined protein and lipid composition.
The synaptic vesicle V-ATPase is an ATP-dependent proton pump that establishes the protein gradient across the synaptic vesicle.
Synaptophysin and its paralogs (synaptoporin and synaptogyrin) are abundant synaptic vesicle proteins.
Synaptophysin knockout mice exhibit severe seizure susceptibility.

Quotes

"Synaptic vesicles are organelles with a precisely defined protein and lipid composition1,2, yet the molecular mechanisms for the biogenesis of synaptic vesicles are mainly unknown."
"We performed structural and functional studies of synaptophysin knockout mice, confirming the identity of synaptophysin as an interaction partner with the V-ATPase."
"In support of this model, we observed that synaptophysin knockout mice exhibit severe seizure susceptibility, suggesting an imbalance of neurotransmitter release as a physiological consequence of the absence of synaptophysin."

Key Insights Distilled From

Structure and topography of the synaptic V-ATPase–synaptophysin complex - Nature

by Chuchu Wang,... at www.nature.com 06-05-2024

https://www.nature.com/articles/s41586-024-07610-x

Deeper Inquiries

How do the structural changes in the V-ATPase-synaptophysin complex affect the specific mechanisms of neurotransmitter uptake and release?

The structural changes in the V-ATPase-synaptophysin complex play a crucial role in modulating the mechanisms of neurotransmitter uptake and release at the synapse. The V-ATPase is responsible for establishing the proton gradient across the synaptic vesicle membrane, which is essential for driving the uptake of neurotransmitters. The interaction between V-ATPase and synaptophysin influences the copy number of V-ATPases in synaptic vesicles, indicating that synaptophysin assists in the biogenesis of these vesicles. This suggests that the presence of synaptophysin impacts the topography of synaptic vesicles, potentially affecting the efficiency of neurotransmitter uptake and release. Therefore, the structural changes in the V-ATPase-synaptophysin complex can directly impact the specific mechanisms involved in neurotransmission at the synapse.

What other synaptic vesicle proteins or lipids might be involved in the biogenesis and regulation of the V-ATPase-synaptophysin complex?

In addition to synaptophysin, several other synaptic vesicle proteins and lipids may be involved in the biogenesis and regulation of the V-ATPase-synaptophysin complex. For example, synaptoporin and synaptogyrin, which are paralogs of synaptophysin, belong to a family of abundant synaptic vesicle proteins. These proteins may also interact with the V-ATPase and play a role in the biogenesis and regulation of the complex. Furthermore, other proteins such as synaptotagmin, synapsin, and VAMP (vesicle-associated membrane protein) could potentially be involved in modulating the function and assembly of the V-ATPase-synaptophysin complex. Additionally, specific lipids present in the synaptic vesicle membrane, such as phosphatidylserine and cholesterol, may contribute to the stability and activity of the complex. Further research is needed to elucidate the full spectrum of synaptic vesicle proteins and lipids involved in the biogenesis and regulation of the V-ATPase-synaptophysin complex.

Could the insights from this study be leveraged to develop therapeutic interventions for neurological disorders associated with synaptic vesicle dysfunction, such as epilepsy?

The insights gained from this study regarding the role of synaptophysin in the biogenesis and regulation of the V-ATPase-synaptophysin complex could indeed be leveraged to develop therapeutic interventions for neurological disorders linked to synaptic vesicle dysfunction, including epilepsy. The severe seizure susceptibility observed in synaptophysin knockout mice suggests that the absence of synaptophysin leads to an imbalance in neurotransmitter release, potentially contributing to epileptic activity. By understanding the molecular mechanisms underlying the interaction between synaptophysin and the V-ATPase, novel therapeutic strategies could be developed to target this complex and modulate neurotransmitter release in a more controlled manner. For instance, small molecules or peptides that mimic the function of synaptophysin could be designed to restore the balance of neurotransmitter release in conditions where synaptic vesicle dysfunction contributes to neurological disorders like epilepsy. Further research in this area could pave the way for innovative therapeutic approaches targeting synaptic vesicle proteins to alleviate symptoms associated with neurological disorders.