Electrical synapse molecular diversity revealed by proximity-based proteomic discovery.

Area of Science:

• Neuroscience
• Molecular Biology
• Proteomics

Background:

• Electrical synapses, crucial for neuronal communication, are less understood molecularly compared to chemical synapses.
• Connexins form the channels of electrical synapses, but their associated protein complexes remain largely undefined.
• The electrical synapse density (ESD) suggests a complex protein machinery beyond gap junctions.

Purpose of the Study:

• To comprehensively identify the proteome associated with electrical synapses.
• To investigate the molecular diversity and compartmentalization within electrical synapses.
• To explore the overlap between electrical and chemical synapse molecular components.

Main Methods:

• Utilized proximity-dependent biotinylation (TurboID) in zebrafish, tagging neural Connexins.
• Performed proteomic analysis on developing and mature nervous systems.
• Examined protein localization within electrical synapse densities (ESD) and their intermingling with chemical synapses.

Main Results:

• Identified hundreds of Connexin-associated proteins, revealing overlapping and distinct sets during development and adulthood.
• Discovered diverse protein classes including cell adhesion molecules, scaffolds, and vesicular trafficking proteins.
• Defined molecular sub-synaptic compartments within ESD and found molecular heterogeneity among electrical synapses.

Conclusions:

• Electrical synapses possess a greater molecular complexity than previously recognized.
• There is a significant overlap in proteomes between electrical and chemical synapses.
• Identified proteins and their human homologs are linked to neurological disorders, offering new research avenues.