New Activation Mechanism For Pain Sensing Channel Revealed

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New Activation Mechanism For Pain Sensing Channel Revealed

http://www.sciencedaily.com/releases/2007/01/070122183022.htm

A group of scientists at the Scripps Research Institute has

identified a mechanism that enables certain compounds to activate a

pain sensing protein. The findings could lead to the development of

potential new therapies for managing acute and chronic pain.

The study was published January 21, 2007 in an advanced online

edition of the journal Nature.

The researchers found that TRPA1, a protein that helps transmit pain

signals, is a direct sensor of reactive chemicals. " While many

noxious and pungent compounds were known to activate this pain

receptor, we discovered that they do so by directly and irreversibly

binding to the cysteine amino acids of this protein, " said Ardem

Patapoutian, a Scripps Research scientist whose laboratory conducted

the study. " Our study shows that TRPA1 activation is directly linked

to chemical insult. "

" Cysteines, one of the twenty building blocks of all proteins, are

known to undergo oxidation/reduction reactions, " Patapoutian

continued. " Somehow the TRPA1 protein is tuned to sense cysteine

modifications. In fact, any cysteine reactive agent seems to

activate TRPA1, although we don't know exactly how cysteine binding

translates into ion channel activation. "

But this activation mechanism comes with an interesting property.

" Generally, compounds that activate ion channels bind in a lock-and-

key mechanism that is readily reversible, " said Lindsey Macpherson,

another author of the study and a Ph.D. candidate in the Scripps

Research Kellogg School of Science and Technology. " The mechanism by

which noxious compounds activate TRPA1 is unique. For example,

compounds that activate an ion channels through a lock-and-key

mechanism have structural similarity. TRPA1 activators have no

structural similarity; instead, they share a common potential for

chemical reactivity, and their binding is long-lasting. "

TRPA1 is not unique among proteins to be activated by cysteine

modifying agents, the study noted. Another signaling protein known

as Kelch-like ECH-associated protein 1 (KEAP1) is activated by many

of the same compounds that activate TRPA1; KEAP1 is a sensor for

oxidative damage from free radicals and upregulates expression of

antioxidant enzymes. Apparently, reactive compounds can activate at

least two pathways through cysteine modification as a warning

against cell damage, the study concluded.

" Our findings, which are the result of a successful collaboration

with the Ben Cravatt and Schultz labs at Scripps Research,

show that modification of reactive cysteines within TRPA1 can cause

channel activation, " Macpherson said. " Our research efforts are now

aimed at further understanding how binding of these compounds

activate the channel, and identifying the physiological role of

TRPA1 in sensing oxidative stress. " The protein is currently being

investigated by several pharmaceutical companies as a potential

target for chronic pain, Patapoutian noted.

Other authors of the study, Noxious Compounds Activate TRPA1 Ion

Channels Through Covalent Modification Of Cysteines, are Adrienne E.

Dubin, J. , Felix Marr, and F. Cravatt of The

Scripps Research Institute; and G. Schultz of The Scripps

Research Institute and Genomics Institute of the Novartis Research

Foundation.

The study was supported by the National Institutes of Health and the

Novartis Research Foundation.

Note: This story has been adapted from a news release issued by

Scripps Research Institute.