FRANKFURT. When two cells “talk” to each other, they often do so through tiny channels called electrical synapses. Unlike chemical synapses, these so-called gap junctions enable the direct exchange of information between two cells, for example in the form of ions. Without them, our hearts could not beat in sync, and nerve cells could not fire in rhythm. But what exactly happens during this form of cell communication?

A Look Inside the Living Cell
Until now, gap junctions have been studied primarily in the form of isolated, chemically treated proteins – that is, outside their natural environment. To image the structure directly in living tissue, researchers from Goethe University Frankfurt (Germany), Max Planck Institute of Biophysics (Germany), and the National Centre for Biological Sciences in Bangalore (India) examined cells of the nematode Caenorhabditis elegans using cryo-electron tomography (cryo-ET). “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 the Institute of Biophysical Chemistry at Goethe University. “From thousands of individual channel images, we then determine a high-resolution structure that provides insight into how the gap junctions function.”

The gap junction channels of the nematode consist of six subunits per cell. Together they form a channel of twelve subunits, exactly as in humans. These structures have been remarkably well preserved during evolution, so that research findings from simple organisms can also be applied to higher mammals. The results showed that not all channels look the same: some were wide and open, others narrow and presumably closed.

Discovery of a Ring-Shaped Cap
On some channels, the researchers discovered an additional structure: a ring-shaped “cap” that sat on the inside of the cell on individual channels and enclosed their opening. This previously undiscovered structure is a tiny but important component: the synapses may be able to regulate their connection with it like a valve – a mechanism that could be crucial for controlling electrical signals in the heart or intestine.
To find out which protein forms this “cap”, the researchers combined their experimental data with AI software that can predict protein structures. The protein UNC-1 matched the observed shape of the cap best. Computer simulations confirmed that the UNC-1 ring can sit stably on the channel and that both proteins interact with each other – as if they were made for each other.

Relevance to Human Diseases
UNC-1 belongs to the family of stomatin-like proteins, which also occur in the human body and can form ring-shaped caps there. Stomatin is found in red blood cells, for example, and the related podocin in the kidneys. Mutations in these proteins in humans are associated with hereditary diseases such as hereditary stomatocytosis or steroid-resistant nephrotic syndrome (SRNS). Nematodes with defective UNC-1 are also severely restricted in their mobility. “The structural similarity of this protein family across different species is remarkable,” says one of the first authors, Nils Rosenkranz, who studied this protein complex for his doctoral thesis. “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 discovery now raises new questions: Does the “cap” actually regulate the opening and closing of the channels? How does it influence the flow of ions? The researchers suspect that human gap junctions could also be regulated by similar caps. In the long term, this could open up new therapeutic approaches for diseases in which communication between cells is disrupted.