SUMO Wrestles With Sodium Channels to Curb Pain
The influx of sodium ions, or lack thereof, determines whether a person feels too much pain, or in some cases, none at all. The UA's Rajesh Khanna is focusing on the "sodium highway," known as the NaV1.7 channel, and a small protein could make the difference.

By Robin Tricoles, University Communications
May 10, 2017


Rajesh Khanna in his lab
Rajesh Khanna in his lab (Photo: Bob Demers/UANews)

University of Arizona pain researchers are seeking to understand how a particular neuron's sodium highway, the NaV1.7 channel — a conduit for sodium ions to pass from the outside of a cell to the inside — regulates its influx of sodium ions.

Regulation is important because the influx of sodium ions, or lack thereof, determines whether a person feels too much pain, or in some cases, none at all.  

As it turns out, people with one type of genetic mutation may be completely insensitive to pain making them vulnerable to serious injuries such a burns or puncture wounds, or even death. Their NaV1.7 sodium channels won't let sodium ions into their cells. Conversely, people with another type of genetic mutation to their NaV1.7 sodium channels feel intense pain with only modest stimuli such exposure to warmth or cold. Their sodium channels allow too many sodium ions to pass through the channel and into the cell.

That's why Rajesh Khanna, professor of pharmacology in the UA College of Medicine, and his collaborators are focusing on the mechanistic understanding of how this protein, and more importantly how modifications of this protein can control the activity of the NaV1.7 channel, and in turn, pain.

Their study is published in the Dec. 27, 2016, issue of PNAS.

"The channel is the conduit for sodium and sodium is what causes the pain," Khanna says. In other words, the channel initiates the pain-signaling pathway.

NaV1.7 channels are plentiful in sensory neurons, cells that detect pain. The channels are embedded in the cell's membrane, with most of the channel residing outside the cell, some within the membrane.

Although there is still much to learn about the mechanisms that govern NaV1.7, Khanna and his colleagues know that NaV1.7 interacts with a protein known as collapsin response mediator protein 2, or CRMP2, which affects the channel's affinity for sodium ions.

They also know that CRMP2 sits inside the cell and interacts, or "talks," with other molecules. And herein lies an opportunity to interrupt or enhance that conversation with other molecules, depending on whether the channel is accommodating too many sodium ions or too few.

"Understanding the mechanism relies on a very simple idea," Khanna says. "If we can figure out what molecule the protein is dialoguing with, we can then try to interfere with that conversation."

Khanna sees promise in a little protein known as a small ubiquitin-like molecule, or SUMO, which would be added to CRMP2, to allow it to have different functionalities to modify sodium-ion uptake.

This subtle approach is quite different from what pharmaceutical companies have focused on in the past when it comes to targeting the NaV1.7 channel, Khanna says. Most companies, he says, are trying to develop channel blockers, which block the entire channel.

But that hasn't worked well when it comes to controlling pain.

"There's a graveyard of failures of these types of drugs," Khanna says. Most prove too toxic to be tolerated.

"Imagine this: You have pain and there are 100 neurons, 60 of them are sensing the pain and firing, where the other 40 are quiescent and happy," Khanna explains. "So, this approach of blocking the channel indiscriminately is going to affect both the 'excitable' pain neurons and the neurons that aren't causing the pain. Blocking the channel is thus like taking a hammer to it. If you block this channel completely, you've lost the ability to feel pain. So, you're like the person with a congenital inability to feel pain. And that's not good."

Instead, Khanna says, we need an approach that's tunable, one where people can maintain the sensation of pain while taking the edge off severe pain. 

Wrestling CRMP2 from getting a SUMO added on to it (much like a henka or sidestep move in sumo wrestling) may be useful in reducing the inflow of sodium and thus controlling too much excitability and thus curbing pain, Khanna says.


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Rajeesh Khanna

UA College of Medicine