Chemical from venom of Chilean tarantula could aid treatment of heart attack, other major diseases

May 15, 2000

BUFFALO, N.Y. -- University at Buffalo biophysicists have identified a component of venom from a very large, very hairy Chilean tarantula that blocks the action of ion channels that are responsible for cellular mechanical responses -- the cell's ability to feel.

These channels or pores in the cell membrane -- called stretch-activated channels because stretching the membrane causes them to open and close -- have been implicated in functions as diverse as the senses of touch and hearing, muscle contraction and coordination, and blood pressure and volume regulation.

This is the first report of a substance -- in this case a small protein -- that specifically blocks stretch-activated channels. Until now, it has been difficult to associate these channels with particular functions because there were no chemical compounds known specifically to block them.

Results of the research appear in the current issue of the Journal of General Physiology. Scientists from the University of Virginia, Michigan State University and NPS Pharmaceuticals collaborated with UB researchers on the study.

The newly identified peptide toxin could have several clinical applications related to cell mechanics, said Frederick Sachs, Ph.D., UB professor of physiology and biophysics, and senior researcher on the project.

"For example, cells swell during congestive heart failure. The peptide interferes with that process. We also know from earlier work that stretching the heart can initiate fibrillation. If we can block the stretch-activated channels, we may be able to block fibrillation, a major cause of death following heart attacks."

Addressing another area, Sachs said tumor invasion of brain tissue produces a deformation of the surrounding normal cells, causing them to release growth factors that may facilitate or accelerate tumor growth. Stretch-activated channels may be the signal for normal cells to release growth factors.

"This peptide blocks those channels and may aid in the treatment of brain tumors," he said. "Stretch-activated channels also play a role in the successful transition of newborns from the placental oxygen supply to using their own lungs."

Having developed a method to observe stretch-activated channels in the laboratory, Sachs and Thomas Suchyna, Ph.D., postdoctoral fellow working with Sachs, set out to find a compound that would block them.

"Basically we went on a fishing expedition, screening things we thought might work," said Sachs. "Eventually, we started looking at the venom of poisonous insects. We didn't know why any bug would possibly make such a thing, but thought it was worth a try."

They first tested scorpion venoms because of their known effect on nerve impulses, but those didn't work. They then ordered up various spider venoms (There are companies that keep and "milk" spiders of all types for research purposes, one of which goes by the name of Spider Pharm) and began screening blindly.

"The venom of two or three spiders had some effect," Sachs said. "One was a tarantula known as Chile Rose. It was a good choice because it is a big spider that produces large amounts of venom."

The scientists then began a painstaking process of separating, or fractionating, the raw venom into its 100-150 different components and testing them to identify the most active component. This turned out to be a 35-amino-acid peptide the researchers labeled GsMTx-4 (for Grammostola spatulata, the spider's Latin name, "M" for mechano, "Tx" for toxin and 4 because it was the 4th peak in the active sequence). Next, to rule out the possibility of a hidden contaminant in the final fraction, Suchyna was able to induce a strain of bacteria to express the pure peptide.

The recombinant peptide blocked the channels as well as the peptide that came directly from the spider, their research showed. Sachs said this result opens the door to studies that require large amounts of peptide, such as determining its three-dimensional structure, that would aid in the design of new drugs.

It also facilitates studies that would look at the effect of the peptide on many cells at once or on whole organs and tissues. Stretch-activated channels are in almost all cells, Sachs noted, giving this peptide potentially wide applications.

The next research phase will involve identifying other biological actions and finding a drug company to turn the peptide into clinically useful drugs.
-end-
The research was funded by grants from the National Institutes of Health, the United States Army Research Office and NPS Pharmaceuticals, Inc.

University at Buffalo

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