Question

The sensations of heat and cold are transduced by a group of temperature-gated cation channels. For example, TRPV1, TRPV3, and TRPM8 are usually closed, but they open at different temperatures. TRPV1 opens at \(\geq 43{ }^{\circ} \mathrm{C}\), TRPV 3 opens at \(\geq 33{ }^{\circ} \mathrm{C}\), and TRPM8 opens at \(<25^{\circ} \mathrm{C}\). These channel proteins are expressed in sensory neurons known to be responsible for temperature sensation. a. Propose a reasonable model to explain how exposing a sensory neuron containing TRPV1 to high temperature leads to a sensation of heat. b. Capsaicin, one of the active ingredients in "hot" peppers, is an agonist of TRPV1. Capsaicin shows \(50 \%\) activation of the TRPV1 response at a concentration of \(32 \mathrm{~nm}-\) a property known as \(\mathrm{EC}_{50}\). Explain why even a very few drops of hot pepper sauce can taste very "hot" without actually burning you. c. Menthol, one of the active ingredients in mint, is an agonist of TRPM8 \(\left(\mathrm{EC}_{50}=30 \mu \mathrm{M}\right)\) and TRPV3 \(\left(\mathrm{EC}_{50}=20 \mathrm{mM}\right)\). What sensation would you expect from contact with low levels of menthol? With high levels?

Short answer

TRPV1 opens for heat; capsaicin mimics heat; menthol feels cool at low levels, mixed at high levels.

Step-by-step solution

Understanding TRPV1 Activation and Heat Sensation

TRPV1 is a temperature-gated cation channel that opens at temperatures higher than or equal to 43°C. When the TRPV1 channel in a sensory neuron is exposed to high temperatures, it opens, allowing cations like Ca²⁺ and Na⁺ to flow into the neuron. This influx of positive ions depolarizes the neuron, triggering an action potential that travels to the brain, where it is interpreted as the sensation of heat.

Effect of Capsaicin on TRPV1

Capsaicin is an agonist of the TRPV1 channel, meaning it can activate the channel without the need for high temperatures. When capsaicin binds to TRPV1, it causes the channel to open, similar to how heat would activate it. The low EC₅₀ value (32 nM) for capsaicin indicates that even at low concentrations, capsaicin can cause significant opening of TRPV1. This is why just a few drops of hot pepper sauce can make it feel hot, as it mimics the sensation of heat by opening TRPV1 channels.

Sensation from Menthol at Different Concentrations

Menthol is an agonist for both TRPM8 and TRPV3 channels. At low levels, menthol activates TRPM8, which opens at temperatures below 25°C and is associated with a cool sensation. Therefore, at low concentrations of menthol, a cooling sensation would be expected. At high concentrations, menthol can also activate TRPV3, which opens at temperatures above 33°C, causing both sensations of warmth and coolness as it stimulates both types of channels. However, the stronger sensation would depend on which channel is more significantly activated due to concentration differences in EC₅₀ values.

Key concepts

TRPV1 activation

The TRPV1 channel is a fascinating biological gatekeeper that gets activated by warmth. It is a type of temperature-gated ion channel found in certain sensory neurons. When temperatures rise above 43°C, the TRPV1 channels open up, allowing cations like calcium (Ca²⁺) and sodium (Na⁺) to flow into the neuron. This influx of positively charged ions causes a change in the electrical potential across the neuron's membrane, also known as depolarization.
This depolarization generates an action potential—essentially an electrical signal—that travels along the neuron to the brain, where it gets interpreted as the sensation of heat. By understanding this mechanism, we can better appreciate how our bodies detect and respond to different environmental temperatures.

Sensation of heat and cold

Temperature sensations, like feeling warmth or chill, are key aspects of how we interact with our environment. Different cation channels open at distinct temperatures to provide these sensations. For example, TRPV1 and TRPV3 are involved in signaling warmth. When opened by heat, TRPV1 channels signal temperatures over 43°C while TRPV3 channels open above 33°C.
Conversely, for cooler sensations, like cold, the TRPM8 channel comes into play. It gets activated as the temperature falls below 25°C. These channels work together to give our nervous system the spectrum of temperature sensations, allowing us to react to various climate conditions with precision.

Effects of capsaicin and menthol

Capsaicin and menthol are chemical compounds that can trick our sensory neurons by mimicking temperature changes. Capsaicin, found in hot peppers, targets the TRPV1 receptor. Even at low concentrations, such as 32 nM, capsaicin can activate TRPV1, which is why spicy foods can "burn" without actual heat. This activation is because capsaicin binds to TRPV1, causing it to open, similar to how it would respond to actual heat.
Menthol, on the other hand, has dual effects. At low levels, it mimics cold by activating TRPM8, giving a cooling sensation. At higher concentrations, it can also affect TRPV3, which may lead to a mixed sensation of warm and cool if TRPM8 and TRPV3 are both stimulated. However, the cooling effect tends to dominate given the lower EC₅₀ value for TRPM8.

Cation channel mechanisms

Cation channels, including TRPV1, TRPV3, and TRPM8, are crucial for temperature sensation. They operate by controlling the flow of positively charged ions across the neuronal membrane. Normally, these channels remain closed, preventing ion flow. However, when a specific temperature threshold is reached for each channel, they open to allow ions like Ca²⁺ and Na⁺ to enter.
This ion influx is essential because it causes the neuron's membrane to depolarize. When depolarization reaches a certain level, it triggers an action potential, essentially an electrical message sent to the brain. This is how the sensation of warmth or cold is communicated. These cation channel mechanisms are central to our ability to perceive environmental temperature changes and maintain homeostasis.