Navigation Links
Tiny proteins have outsized influence on nerve health

Mutations in small proteins that help convey electrical signals throughout the body may have a surprisingly large effect on health, according to results of a new Johns Hopkins study study published in Proceedings of the National Academy of Sciences in December using spider, scorpion and sea anemone venom.

The tiny conduits carrying those electrical signals are sodium channels that are vital to our well-beingthey trigger action potentials, or spurts of electrical energy that course from body to brain to deliver messages that invoke feelings like pain or temperature sensitivity. When such channels go awry, they contribute to a slew of diseases, one of which is epilepsy.

In the new research, Frank Bosmans, Ph.D., an assistant professor of physiology at the Johns Hopkins University School of Medicine, has found that auxiliary "helper" proteins that interact with sodium channels also play a crucial role. And that, he says, could affect drug development for epilepsy, neurological diseases, muscular disorders and pain syndromes.

"Nobody had thought these tiny molecules that don't even form the main sodium channel were capable of changing the response of the channel to certain compounds," Bosmans says. "But in what we consider a new concept, these auxiliary subunits can be considered as drug targets."

Over the past few decades, there have been hints that these auxiliary proteins were influencing sodium channels, but few analyzed the problem very closely. John Gilchrist, a graduate student in Bosmans' lab, began evaluating each of the four proteins, one at a time.

Gilchrist engineered frog eggs that made sodium channels and exposed them to the toxins released by tarantulas, scorpions, wasps and sea anemones, an extension of Bosmans' earlier doctoral research studying the effect of animal venoms on sodium channels. He found that one auxiliary protein in particular, beta4, altered the whole sodium channel system. When exposed to tarantula venom, for instance, tissue in the presence of beta4 showed decreased sensitivity in the sodium channels, meaning that the protein changed the way the nerve fired. This denotes that if a human got bit by a tarantula in a region where beta4 was active, the whole experience might be just a little less painful, says Bosmans.

To figure out what was going on in the altered channels, Bosmans needed to know what the protein looked like, he says. He contacted Filip Van Petegem, a crystallographer at the University of British Columbia in Vancouver, Canada. Van Petegem was able to map the 3-D structure of beta4 down to 1.7 angstroms, the highest possible resolution. Crystal structure in hand, Bosmans could now mutate beta4 and watch what happened.

Purely by chance, Van Petegem had already started that mutation process. To diagram the crystal, Van Petegem had been forced to substitute one protein for another due to quirks in the test system. Bosmans found that the tiny mutation thwarted beta4's interaction with the sodium channel system.

That finding promptly overturned conventional wisdom into how these proteins behave, Bosmans says.

Back in 1998, Bosmans says, physicians determined that a mutation in the beta1 protein seemed to be triggering a case of epilepsy. Epilepsy has hundreds of causes. It was known at the time that a chemical bridge within the sodium channel held the beta proteins together. If that bridge, known as a disulfide bond, is broken, the proteins fall apart. The physicians theorized that the mutation they found must have destroyed the bridge along with their accompanying proteins. That broken bridge theory has remained dominant ever since.

But when Bosmans introduced that same mutation in beta4, the structure stayed intact. The changes he saw were much more subtle. The position of the protein Van Petegem had mutated changed slightly so that it was farther away from the channel. And only when that mutated crystal was exposed to a toxin did beta4 lose its ability to communicate with the sodium channel.

Bosmans says that even with evidence of the auxiliary proteins' importance mounting, such as in the epilepsy study, drug developers have continued to ignore the proteins rather than treatment opportunities. Most efforts to develop new drugs to treat epilepsy still focus exclusively on modifying the sodium channels, which don't need the beta proteins to operate. But Bosmans believes this is only part of the story.

His new finding suggests that such an approach is shortsighted, because mutations in these beta proteins may very well be causing the disease at hand. Drugs that target the beta proteins have the potential to deliver a much more focused treatment, he says.

"That's one of the new concepts that we're trying to launchkeep an eye on these little guy proteins, because they are important. If they have a mutation in them, they can cause a disease," Bosmans says.


Contact: Vanessa McMains
Johns Hopkins Medicine

Related biology news :

1. More effective method of imaging proteins
2. Gold nanoantennas detect proteins
3. Discovery of a new family of key mitochondrial proteins for the function and viability of the brain
4. Discovery of plant proteins may boost agricultural yields and biofuel production
5. UCLA researchers develop way to strengthen proteins with polymers
6. Discovered a new checkpoint of cell cycle control through joint action of 2 proteins
7. A non-invasive intracellular thermometer with fluorescent proteins has been created
8. Speeding up drug discovery with rapid 3-D mapping of proteins
9. Identification of differential proteins in maternal serum with Down syndrome
10. Neiker-Tecnalia identifies antitumour proteins in the latex of the plant Euphorbia trigona
11. The appetite-suppressing effect of proteins explained
Post Your Comments:
(Date:11/19/2015)... 2015  Based on its in-depth analysis of the ... with the 2015 Global Frost & Sullivan Award for ... presents this award to the company that has developed ... of the market it serves. The award recognizes the ... on customer base demands, the overall impact it has ...
(Date:11/18/2015)... New York , November 18, 2015 ... Market Research has published a new market report titled ... Growth, Trends, and Forecast, 2015 - 2021. According to the ... in 2014 and is anticipated to reach US$29.1 bn ... to 2021. North America ...
(Date:11/17/2015)... , Nov. 17, 2015  Vigilant Solutions announces ... joined its Board of Directors. --> ... after recently retiring from the partnership at TPG Capital, ... companies with over $140 Billion in revenue.  He founded ... across all the TPG companies, from 1997 to 2013.  ...
Breaking Biology News(10 mins):
(Date:11/25/2015)... ... 25, 2015 , ... A long-standing partnership between the Academy ... been formalized with the signing of a Memorandum of Understanding. , AMA Executive ... Karl Minter and Capt. Albert Glenn Tuesday, November 24, 2015, at AMA Headquarters ...
(Date:11/24/2015)... ... 24, 2015 , ... The United States Golf Association (USGA) today announced Dr. ... Award. Presented annually since 1961, the USGA Green Section Award recognizes an individual’s distinguished ... , Clarke, of Iselin, N.J., is an extension specialist of turfgrass pathology in ...
(Date:11/24/2015)... ... November 24, 2015 , ... International Society for ... of the premier annual events for pharmaceutical manufacturing: 2015 Annual Meeting. The conference ... ISPE hosted the largest number of attendees in more than a decade. ...
(Date:11/24/2015)... (PRWEB) , ... November 24, 2015 , ... The Academy ... Special Interest Group (SIG), MultiGP, also known as Multirotor Grand Prix, to represent the ... last few years. Many AMA members have embraced this type of racing and several ...
Breaking Biology Technology: