Newly Discovered Gap Junction Caps Help Tune Electrical Synapses

Electrical synapses, also known as gap junctions, allow the direct exchange of information between two cells, and are essential for synchronized heartbeats and rhythmic nerve activity. In a study published recently in Science Advances, researchers examined how these channels are organized inside living cells and identified an additional ring-shaped “cap” structure that may modulate their opening and closing.

Using cryo-electron tomography on cells from Caenorhabditis elegans, the team imaged gap junctions in their native environment rather than as isolated, chemically treated proteins. “With this method, we can freeze the cells in their natural state and take three-dimensional images of their interior,” explains Prof. Dr. Alexander Gottschalk from Goethe University, noting that thousands of channel images were combined to obtain a high-resolution structure that reveals how the junctions operate. The channels consist of six subunits per cell, forming a 12-subunit intercellular channel, mirroring the organization found in humans.

The images showed structural diversity among channels, with some appearing wide and open and others narrow and presumably closed. On a subset of channels, the researchers detected an additional ring-shaped “cap” on the cytoplasmic side, enclosing the channel opening. This small feature may allow synapses to regulate connectivity like a valve and could be important for controlling electrical signals in tissues such as the heart or intestine.

To identify the cap-forming protein, the researchers integrated their structural data with AI-based protein structure predictions. The stomatin-like protein UNC-1 best matched the observed ring and computer simulations indicated that an UNC-1 ring can bind stably to the channel, with both components interacting closely. Nematodes lacking functional UNC-1 display severe movement defects, underscoring the biological relevance of this interaction.

UNC-1 belongs to a conserved protein family that includes stomatin in red blood cells and podocin in the kidney, both of which can form ring-shaped caps and are linked to human disorders such as hereditary stomatocytosis and steroid-resistant nephrotic syndrome. “The structural similarity of this protein family across different species is remarkable,” says first author Nils Rosenkranz. “Our discovery suggests that the regulation of gap junctions or other channels in the cell membrane by such caps could be a fundamental principle of cell communication—from nematodes to humans.”

The work raises several open questions, including whether the cap directly controls channel gating and ion flow and whether human gap junctions are regulated by similar structures. The researchers suggest that understanding this mechanism may eventually inform strategies for diseases involving impaired cell-to-cell communication.