Shape-shifting cell channel reveals new target for precision drugs

From small ions to large molecules, cellular gates control what can pass in and out of cells. But how one such gate, called pannexin-1 (PANX1), can handle vastly different cargo sizes has remained a long-standing mystery.

In a new study, Northwestern University scientists uncovered the molecular trick behind PANX1’s versatility. The channel dilates and constricts — just like the iris of an eye — to control the flow of chemical messages, which influence everything from brain activity to inflammation and even fertility. 

The findings show that PANX1 isn’t a rigid channel but a shape-shifting molecular valve that can dynamically resize to accommodate both tiny particles and bulky signaling molecules.

The researchers also found that a common, decades-old malaria drug holds the key to controlling this gate. The drug binds to a newly identified pocket within the PANX1 channel to fine-tune its opening and closing. By manipulating this mechanism, scientists could one day develop therapies that rebalance cellular communication — restoring order in conditions linked to inflammation, nerve signaling, reproductive health and more.

The study was published today (Dec. 11) in the journal Nature Communications.

“PANX1 has been linked to many different diseases, including cardiovascular disease, neurological disorders, chronic pain and muscular dystrophy,” said Northwestern’s Wei Lü, who co-led the study with Juan Du. “But existing drugs that inhibit PANX1 block the main channel, shutting down all its activity including normal functioning. That causes unwanted side effects. We identified a new binding site in a side channel that gives us a basis for developing more selective drugs, which could fine-tune PANX1 rather than silencing it completely.”

Lü and Du are professors of molecular biosciences at Northwestern’s Weinberg College of Arts and Sciences, professors of pharmacology at the Feinberg School of Medicine and members of Northwestern’s Chemistry of Life Processes Institute. Yangyang Li, a postdoctoral fellow in the Lü and Du Labs, and Zheng Ruan, a former postdoctoral fellow who is now an assistant professor at Thomas Jefferson University, are the study’s lead authors.

Found in the membranes of many cell types throughout the body, PANX1 enables cells to release multiple molecules, including adenosine triphosphate (ATP). Although ATP is best known for carrying energy inside cells, it also acts as a powerful signaling messenger outside cells. ATP signals allow cells to communicate with one another, so tissues can coordinate immune responses, wound healing and fertility.

In 2020, Lü and Du published a study in Nature, in which they constructed a near-atomic blueprint of PANX1. The blueprint revealed seven hidden, narrow side tunnels branching off the main channel.

“That discovery overturned a long-standing assumption that all of the signaling happened through a single channel,” Du said. “Uncovering the side tunnels opened up a whole new dimension for understanding how PANX1 functions.”

To explore this system further, the team used cryo-electron microscopy (cryo-EM) to capture high-resolution snapshots of PANX1 channels in different states. They also performed electrical recordings to measure activity within the channels and used computer simulations to model how molecules move through PANX1’s pathways.

Lü, Du and their team found a ring of amino acids form a flexible gate at the channel’s outer opening. This ring shifts between two positions. When constricted, only small ions can pass. When dilated, larger molecules like ATP can slip through.

“It widens to release ATP and then tightens back down to only let smaller molecules, like chloride ions, get through,” Lü said. “Being able to switch between these two modes is essential for how PANX1 does its job. Watching that happen was like seeing the gatekeeper of cellular communications at work.”

The researchers also discovered that mefloquine, an FDA-approved antimalarial drug, binds to a previously unknown pocket near one of the side tunnels — not in the main channel — of PANX1. Rather than blocking PANX1, mefloquine enhances its activity, allowing more ions to flow through. 

This finding identifies the first known drug site capable of boosting, not just inhibiting, PANX1’s function. It opens the door to designing precise, targeted therapies that can either amplify or dampen the channel’s activity depending on the therapeutic need.

The study, “Structural basis of PANX1 permeation and positive modulation by mefloquine,” was supported by the National Institutes of Health, a McKnight Scholar Award, Klingenstein-Simon Scholar Award, Sloan Research Fellowship and a Pew Scholar in the Biomedical Sciences award. The researchers also received support from the Structural Biology Facility (SBF) for cryo-EM data collection and computational support from Northwestern IT Research Computing and Data Services.