Scientists determine that connexin molecules allow cells to send messages to each other

Researchers have gained new insights into how drugs bind to connexin molecules. These molecules form channels that allow neighboring cells to send each other direct messages. Dysfunctions of these channels are implicated in neurological and cardiac diseases. The new understanding of how drugs bind and affect each other should help develop therapies to treat such conditions.

Today we use many electronic means to communicate, but sometimes dropping a message in a neighbor’s mailbox or leaving a cake on the doorstep is more effective. Cells also have ways to send direct messages to their neighbors.

Adjacent cells can communicate directly through relatively large channels called gap junctions, which allow cells to freely exchange small molecules and ions with each other or with the outside environment. In this way, they can coordinate the activities of the tissues or organs they compose and maintain homeostasis.

These channels are created from proteins called connexins. Six connexins located in the cell membrane create a hemichannel; this hemi-channel joins with a hemi-channel in a neighboring cell to create a bidirectional channel.

When connexin channels do not function properly, they cause changes in intercellular communication that have been linked to many different diseases. These include cardiac arrhythmias, central nervous system diseases such as epilepsy, neurodegenerative diseases and cancer.

As a result, the search for drugs targeting connexins is ongoing. Yet, understanding of the structure of connexins and how drugs bind to connexin channels to block or activate them is limited. Indeed, among the 21 types of connexins known to exist in humans, few of them are currently being evaluated as drug targets.

An explanation of the side effects of antimalarials?

Now, researchers from PSI, ETH Zurich and the University of Geneva have deepened our understanding of connexin channels and how they bind to drug molecules. The study is published in the journal Cellular discovery.

The connexin they studied is known as connexin-36, or Cx36 for short. Cx36 plays important roles in the pancreas and brain, controlling insulin secretion and neuronal activity, respectively. Increased levels of Cx36 channels have been observed in patients with epilepsy following head trauma. Here, the increased activity of gap junction channels is thought to cause neurons to die. So the team looked for drugs that inhibit these channels.

The team studied Cx36 linked to the antimalarial drug mefloquine (brand name Lariam). The drug is known to act on malaria-causing parasites when they enter the bloodstream of infected mosquitoes. However, research has indicated that mefloquine also binds to Cx36 in our cells, potentially explaining some of the drug’s well-known serious neuropsychiatric side effects.

Using cryo-electron microscopy, the research team captured high-resolution structures of the Cx36 gap junction channels with and without the presence of mefloquine. They saw how the drug molecule binds to each of the six connexins that make up the channel. The binding site is buried in the pores of the channel, so when six molecules bind, they effectively close the channel.

Computer simulations performed by collaborators at the University of Geneva helped the team understand the effect that mefloquine binding would have on the channel’s ability to pass ions. In this way, they showed that drug binding limits the flow of solutes through the channel.

A starting point for drug discovery based on the structure of connexins

The researchers hope that this new structural knowledge will provide a starting point for developing new drugs that are more specific for particular connexin channels.

“Our study shows how a drug molecule lands in the pores of the channel and gives, through our simulations, a plausible explanation of how the drug inhibits the channel,” explains Volodymyr Korkhov, group leader at PSI and associate professor at the ‘ETH Zurich. who led the study. “This relates not only to Cx36, but also to the broader question of connexin-drug interactions.”

The latest findings complement other research on connexins from the PSI/ETHZ group: including the structure of connexin 43 in a closed conformation and how structure and function are linked in connexin 32, which plays a role in the peripheral nervous system .