University at Buffalo - The State University of New York

Published: July 15, 2004

By LOIS BAKER
Contributing Editor

A tarantula venom peptide, GsMTx4, known to affect many organs, can be manipulated to withstand destruction in the stomach, making it a promising candidate for drugs that could treat cardiac arrhythmias, muscular dystrophy and many other conditions, UB biophysicists have shown.

Moreover, the peptide, which is amphiphilic—meaning fat-soluble on one side and water-soluble on the other, much like a detergent—affects mechanically sensitive ion channels in membranes in a manner totally different than the standard "lock-and-key" binding mechanism.

Results of the research appear in the July 8 issue of the journal Nature.

The peptide is the only agent known to specifically block stretch-sensitive channels. Unlike other membrane channels that are sensitive to electrical potential or the binding of hormones and neurotransmitters, stretch-sensitive channels are activated by changes in membrane tension.

"Stretch-sensitive channels can play a key role in many normal tissue functions," said Tom Suchyna, research associate in the Center for Single Molecule Biophysics and first author on the paper. "These channels are involved in hollow-organ filling such as the bladder, in heart and circulatory-system responses to changes in blood pressure, proprioception—knowing where your limbs and head are in space and time—and fluid balance.

"They also are involved in abnormal tissue functions, such as cardiac arrhythmias, congestive heart failure, elevated calcium levels in muscular dystrophy and angiogenesis-supported tumor growth."

Earlier research by the UB group had shown that the novel peptide inhibits stretch-sensitive channels, but the researchers didn't know how. To gain more information on the peptide's possible receptor, Philip Gottlieb, a co-investigator from the Department of Physiology and Biophysics and the Center for Single Molecule Biophysics, created a mirror image of the molecule, referred to as "right-handed," to observe the peptide-membrane interaction.

Since almost all proteins in nature are "left-handed," right-handed proteins won't fit into a left-handed receptor, even if they have the same amino acid sequence. "It's like putting your right foot into your left shoe," said Suchyna.

In this case, however, they found that both proteins inhibited stretch-sensitive channels. "If the right-handed GsMTx4 works as well as the left-handed, it must be interacting with the stretch-activated channel by changing the tension that the channel senses in the membrane, rather than locking onto the channel," he said. "This leads us to believe that there is something unique about the membrane that surrounds stretch-sensitive channels, and that this special membrane environment attracts GsMTx4. That would explain why this peptide blocks only this type of channel."

In addition to providing valuable information on how the peptide works, the finding that both versions blocked the channels makes the peptide an attractive drug candidate. "This was an awesome tool to find," said Fred Sachs, professor of biophysics in the Center for Single Molecule Biophysics and senior author on the study.

"Peptides usually don't make good drug candidates. They can't be given by mouth because the stomach enzymes digest them, and they can cause an immune response. But because this peptide works in its right-handed form, and the normal left-handed digestive enzymes and left-handed antibodies don't recognize it, oral administration is a definite possibility. It may be more than a lead compound for drug development. It may work just as it is.

"If this prognosis proves correct," said Sachs, "the peptide could be an effective treatment for atrial fibrillation, incontinence, muscular dystrophy, high blood pressure and other conditions governed by stress-sensitive channels."

Suchyna said the next steps will be to investigate the environment surrounding the channels, to study the role of stretch-activated channels in cardiac arrhythmias and to mutate the peptide to make it specific for different tissues.

Studies of these peptides on a model ion channel called gramicidin, reconstituted in artificial lipid membranes, were carried out by Sonya E. Tape, a graduate student, and Olaf S. Anderson, both from the Weill Medical College of Cornell University, and Roger E. Koeppe II, from the University of Arkansas.

The research was supported by grants from the National Institutes of Health.