Neuroscientists Explore Temperature-Sensitive Pathways to Control Neural Activity
Madison, Wisconsin - The body senses heat and cold at a molecular level, sending signals to the cell and the entire body to react to the environment. But if scientists can unlock the potential of these temperature-sensitive signaling pathways, the field of neuroscience could have an entirely new way to study the brain. That’s why researchers at the University of Wisconsin-Madison have built their own pathway.
While mad scientists with plans for world domination via mind control may take interest, controlling neural activity is more applicable to developing new models for studying how the 200 different kinds of neurons in the brain interact, send and receive signals, process sensory input, and form and retrieve memories.
Temperature sensors are ubiquitous in nature but remain poorly understood. In a study published online by Cell, UW School of Medicine and Public Health scientists re-engineered a normal, voltage-dependent potassium ion channel and made it either heat or cold-sensitive, demonstrating the plausible molecular mechanics and structure necessary to make a temperature-sensing ion channel.
Importance of Temperature-Sensitive Signaling
Temperature-sensitive signaling plays an important role in pain pathways and is considered an important target for treating chronic inflammation and neuropathic pain. Interestingly, many of these heat sensors also respond to things like capsaicin, which provides that burning sensation when you eat chili peppers. The cold-sensitive channels also respond to ‘cooling’ chemicals like menthol or camphor.
Specialized ion channels called the TRP channels found in the cell membranes of higher organisms mediate temperature-dependent responses. Ion channels are proteins that act like pores in the membrane, letting ions pass through in response to a physical or chemical stimulus. This movement of ions is what generates electrical signals up and down your arm when you touch something hot.
“The temperature-sensing TRP channels respond very sharply to changes in temperature, and it seems like their sensitivities are finely tuned to very specific temperature ranges,” said Baron Chanda, associate professor of neuroscience at the UW School of Medicine and Public Health and senior author on the paper. “Heat-sensitive channels seem to respond when the temperature goes up to 37 to 42 degrees Celsius (98.6 to 107.6 F), and cold-sensitive channels sense temperatures from 20 to 15 degrees Celsius (68 to 56 F).”
Since the discovery of the first temperature-activated ion channels, research over the past decade and a half has led to competing theories of how these molecules sense temperature. Given their similarity to voltage-gated ion channels it was suggested that temperature modulates voltage-sensitivity of these ion channels.
Others believe that there are specialized temperature-sensing modules within the ion channels that respond to temperature. Despite much effort, no consensus has emerged regarding the nature or identity of this temperature-sensing domain.
“We put these theories to test by taking a design approach. We took a temperature-insensitive potassium ion channel and systematically introduced mutations in that protein to make it either heat or cold-sensitive,” said Chanda. “We found to our surprise that very few mutations are required to make this potassium channel as sensitive as a naturally occurring temperature-sensing ion channel. Our experiments show for the first time that some of these theories can account for all temperature sensitivity of the TRP ion channels.”
The UW researchers found that they could make the voltage-sensitivity of the potassium channels highly temperature-dependent by introducing amino acids that either release or absorb heat when they are exposed to water molecules. These amino acids were placed at locations that undergo changes in water exposure when the ion channel opens or closes.
In addition, the researchers also found that reducing the voltage-sensitivity increases the temperature sensitivity. This illustrates a key thermodynamic principle of load sharing and explains why all temperature-sensitive ion channels have reduced voltage sensitivity.
Not Science Fiction
Aside from providing fundamental insights into the mechanisms of temperature-sensation, these studies provide general principles to design novel temperature-sensitive ion channels that will likely affect the study of brain function. Two new ways of studying the brain may seem more like science fiction, but optogenetics - controlling neurons with light - and thermogenetics - controlling neurons with temperature - are very real.
And while there have already been some compelling advances in optogenetics, it has its drawbacks. Activating or deactivating those neurons with light requires invasive equipment, like inserting a fiber optic cable in the brain. Heat, in contrast, can be delivered using infrared or microwaves or even ultrasound, which penetrates tissue to a much greater degree while being less invasive.
Date Published: 08/21/2014