Too hot to handle! Scientists identify heat sensing regulator

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Too hot to handle! Scientists identify heat sensing regulator

http://www.eurekalert.org/pub_releases/2008-05/jhmi-tht051308.php

Neuroscientists at s Hopkins are a step closer to understanding

pain sensitivity - specifically why it's variable instead of

constant - having identified a gene that regulates a heat-activated

molecular sensor.

Their description of the function of a membrane protein called Pirt

appears in the May 2 issue of Cell.

" Pain sensitivity increases during inflammation or injury and we want

to know what molecules are involved in pain sensation when

sensitivity is elevated, " says Xinzhong Dong, Ph.D., an assistant

professor of neuroscience at Hopkins.

The ability to sense temperature heat and spice is controlled by the

TRPV1 protein channel found on the surface of certain nerve cells. In

an inactive state, TRPV1 channels remain closed-there is no pain

sensation. However, when noxious heat-temperatures above 108 degrees

Fahrenheit-or capsaicin-the main ingredient in " hot " peppers-

activates a TRPV1 channel, ions flow through, depolarizing the nerve

to create an electrical current that sends pain signals to the brain.

" The interesting thing about this channel is it's not always

constant, " says Dong, whose team set out to find proteins that

modulate TRPV1's action. They found the Pirt protein,phosphoinositide

interacting regulator of TRP, and named it for its ability to

regulate the TRPV1 channel.

To better understand how Pirt works, the researchers made mice that

lacked Pirt and tested their ability to respond to heat. The mice

were placed on a hot surface and monitored for how long it took them

to scurry off. Mice lacking Pirt responded significantly slower than

normal mice.

The team then exposed one hind paw to capsaicin and found that mice

lacking Pirt did not lick their paws as long as normal mice,

suggesting that without Pirt, they were compromised in their ability

to sense the spice of capsaicin. The researchers also tried mustard

oil on the hind paw and found mice lacking Pirt licked for about the

same amount of time as normal mice. These observations suggest that

Pirt's action is specific to capsaicin and not other chemicals.

To figure out whether Pirt directly affects TRPV1 channel action, the

researchers measured electrical currents generated by TRPV1 in single

nerve cells with or without Pirt. They exposed some nerves to noxious

heat-108 degrees Fahrenheit-and some nerves to capsaicin and compared

currents generated in each cell. Cells containing Pirt generated

stronger currents in heat and spice than cells lacking Pirt, leading

the researchers to conclude that Pirt is required for a full pain

response to both heat and spice.

Further research revealed that Pirt interacts with yet another

molecule in the cell, a so-called acidic phospholipid, allowing

access to TRPV1. According to Dong, through this phospholipid Pirt

somehow changes the TRP channel, perhaps by opening it wider, or

maybe by causing it to stay open longer. And the result is elevated

pain sensitivity.

Exactly how Pirt regulates the TRPV1 channel isn't yet clear, says

Dong. " The goal is to find molecules that specifically affect the

pain pathway, but not other nerves, " he says. " We're looking for

genes specifically turned on in pain-sensing neurons. If we find them

and can target them with new drugs, we will be able to treat pain

without unfavorable side effects. "