Neuroscience 2016: Thermosensors

Neuroscience 2016: Part 1 | Thermosensors | Pain Research Forum – David Julius delivers sweeping history of thermosensors in featured lecture at Society for Neuroscience annual meeting – by Stephani Sutherland on 31 Jan 2017

Summary of a featured lecture delivered by David Julius, University of California, San Francisco. The lecture discussed the use of natural compounds to understand the structure and function of the TRPV1 ion channel.

Spicy plants and venomous beasts are the sources of natural products that have been used for decades to study neurophysiology. Rather than look for pain-relieving substances, Julius said he wanted to “flip the coin and find compounds that would activate pain.”

From a long list of compounds, a few emerged that could selectively activate pain-sensing nerve fibers, including capsaicin, menthol—which is cooling but can be painful—and isothiocyanates, volatile substances found in onions and other plants.  

In addition to activating sensory neurons, these compounds also elicit the release of inflammatory mediators such as substance P, calcitonin gene-related peptide, and adenosine triphosphate.

A polymodal signal integrator

The TRP family of channels is diverse in function.

The TRP channels important to somatosensation—namely TRPV1, TRPM8, and TRPA1—are activated by compounds found in nature, but also by intrinsic factors such as temperature and endogenous inflammatory substances

TRPV1 opens in response to capsaicin and temperatures above 45 degrees Celsius—the point at which people discern painful heat—whereas TRPM8 is activated by menthol and by temperatures below 26 degrees Celsius

But rather than simply functioning as the body’s heat detector, TRPV1 is now recognized as a polymodal signal integrator, Julius said.

The channel can be modulated or opened by ingredients in the “inflammatory soup” found at sensory nerve endings after injury.

A closer look at TRPV1

Julius and colleagues at UCSF have focused on studying how the TRPV1 channel opens and moves, and how that might be exploited to diminish TRPV1 activity

Investigators suspected that TRPV1’s structure resembled that of voltage-gated potassium channels

As expected, the channels contained four identical subunits with a structure similar to potassium channels.

TRPV1 contains two “gates” within the pore that control the flow of ions.

When RTX or DkTx bind to the channel, Julius said, “those gates are blown wide open.”

Why would a channel need two separate gates? That’s not clear, but Julius said, “evolutionarily, it affords the channel rich opportunities for channel modulation—and for drug intervention.”

The data also allowed researchers to see a phosphoinositide lipid bound within the channel in the capsaicin-binding pocket, suggesting that such molecules serve as endogenous ligands at TRPV1.

“The findings tell us how capsaicin works, but also how lipids play an endogenous role at the channels,” Julius said, “such as phosphatidylinositol bisphosphate, anandamide, N-arachidonyl dopamine, and possibly others.”

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