Molecular thermometers on skin cells detect heat and camphor

The human brain is like a general in a bunker. Floating in its bubble of cerebrospinal fluid, it has no direct window to the outside world, so the only way for the brain to observe, comprehend, and order the body into action is to rely on information it receives. This information comes to it through a sophisticated system of sensory neurons that connect the brain to organs like the eye, ear, nose, and mouth.

In recent years, biologists and neuroscientists have been trying to discover the basic molecules and mechanisms that underlie this complicated communication system that is our senses, and one group of researchers from The Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation (GNF), has been making headway in trying to understand those that mediate our sense of touch.

Touch is perhaps the most fundamental of our five senses because it works through our largest organ, the skin. Through the skin we can detect temperature, texture, and understand both pleasure and pain. A few years ago, the Scripps Research and GNF team, which was led by Scripps Research Assistant Professor Ardem Patapoutian, was the first to clone a protein (TRPV3) that the researchers believed was involved in our ability to sense and detect warm temperature. But while temperature-gated action of TRPV3 suggested the protein might be communicating temperature to the brain, its distribution raised some doubts. Despite expectations that temperature sensors be present in sensory neurons innervating the skin, TRPV3 protein was found in actual skin cells (keratinocytes) and not in the neurons.

Now, in the latest issue of the journal Science, the team is reporting definitive evidence that TRPV3 is indeed a temperature sensor. They have demonstrated that mice lacking the TRPV3 protein have specific deficiencies in their ability to detect temperatures. “Are the TRPV3 proteins involved in heat sensation in the living mammal?” says Patapoutian. “The answer seems to be ’yes.’”

This is significant because it suggests that TRPV3 is a potential drug target. TRPV3 is one of many receptors that participate in signaling pain–an indication for which there is a great need for new therapeutics. Indeed, several compounds that are currently under investigation for alleviating chronic pain target the action of a protein called TRPV1 (VR1), which is similar to TRPV3.

Molecular Thermometers

TRPV3 and TRPV1 are both proteins that belong to a class of molecules known as “transient receptor potential” channels. There are at least six of these TRP channel proteins in humans and other mammals, and there has been growing evidence in the last few years that these proteins are “molecular thermometers” that detect hot and cold temperatures through the skin and communicate the sensation of temperature to the brain.

The most obvious evidence is that TRP channels are activated by thermal heat within a particular temperature range–from the extremely cold to the extremely hot. TRPV3, for instance, becomes activated at warm and hot temperatures of 33° C (91.5° F) and above. Similarly, other TRP channels are specifically activated within hot, warm, cool, or cold temperature ranges.

Most of these temperature-gated channels are also located where scientists would expect the molecules that communicate temperature to the brain to be located–in the sensory neurons that connect the skin to the spinal column and the brain. These proteins become activated when they receive the correct stimuli (such as a certain temperature), and this causes them to open and allow electrically charged ions to pass through and cause an electrical potential that signals the brain.

Patapoutian and his colleagues discovered TRPV3 a few years ago by conducting a computer search through an early-assembled draft of the human genome. Its sequence similarity to other temperature-gated proteins led them to identify and clone TRPV3 as a possible molecular thermometer–perhaps the first one that makes skin cells able to sense warm temperatures.

Now they have demonstrated that the receptor does indeed detect heat by examining the physiological and behavioral characteristics of a knockout mouse with no TRPV3 proteins. The mice appear completely normal behaviorally except that they have severe deficiencies in their ability to detect warm and hot temperatures. Patapoutian and his colleagues also showed that, in cultured keratinocyte cells, TRPV3 is activated by the compound camphor, which is one of the main ingredients in many warming rubs. TRPV3 is the first known receptor for camphor.

Significantly, when Patapoutian and his colleagues discovered TRPV3 a few years ago, they were intrigued to discover that it is unique among thermoTRP channels in that it is expressed on the surface of skin cells known as keratinocytes. At the time, they hypothesized that its presence on keratinocytes might mean that the detection of temperature takes place in the skin as well as on these neurons.

In their Science paper, they demonstrate that this is indeed the case by showing that camphor activates TRPV3 on keratinocytes but not on sensory neurons. In the knockout models, this heat- and camphor-mediated activity disappears, which suggests that it is the TRPV3 proteins on the keratinocytes that are actually detecting warm temperatures. It is not known how this signal is communicated to the brain, since keratinocytes, unlike neurons, have no direct link with the central nervous system. Keratinocytes do, however, touch nerve fibers, and it may be through these contacts that the signals are communicated. Investigations into this possibility are ongoing.