Noxious and downright painful stimuli are a given in every life, but they also often provide useful warnings to get out of harm’s way.
David Julius, PhD, a UCSF biochemist and molecular biologist, has made great strides in sorting out what’s behind our invaluable ability to sense hot, cold, and chemical irritants. To accomplish this, he and his lab team often use organisms with their own noxious – you might say obnoxious – ways of defending themselves. For instance, did you know that the same pain receptor and nerve pathways are engaged when you feel the burn of a hot chili pepper as when you experience a venomous tarantula bite? But far beyond the realm of gee-whiz science, spider wrangling or Habañero-eating challenges, Julius’ studies of thermosensation and pain sensation are important for understanding chronic pain syndromes that often are triggered by tumor growth, infections or other types of injury. For his accomplishments, Julius, chair of the Department of Physiology at UCSF, has been named to receive the prestigious Passano Award this year. The award honors U.S. research that leads to clinical medical applications. Previous winners include UCSF Nobel laureates Elizabeth Blackburn, PhD, J. Michael Bishop, MD, and Harold Varmus, MD. Julius will lecture on his discoveries and accept the award during a Passano Foundation meeting in Baltimore on April 26.
Hot Today, Chili Tomorrow
Julius’ strategy for seeking out molecules that play a critical role in signaling a painful touch or temperature is to track them down with the help of drugs or natural products that trigger the same sensations and perceptions. Julius along with his students and postdoctoral fellows sought to discover how the component responsible for the spicy hotness of chili peppers – called capsaicin – elicits a burning sensation that sends us reaching for the water pitcher to quench it. The research led to the identification and cloning of the specific protein responsible, named TRPV1.
TRPV1 is a specialized ion channel located at the outer tips of sensory nerves. Ion channels are pores that open and close to govern the movement of electrically charged atoms – called ions – across cell membranes. Nerve cells transmit electrical signals along their length as a result of transient changes in electrical potential across the outer membrane of the cell. These transient changes result from the successive opening and closing of ion channels. The rapid changes in electrical potential enable the sensory signal to travel through the cell’s branching connection to a neighboring nerve cell – like a wave, or like falling dominoes.
TRPV1 is triggered by capsaicin. Remarkably, it also is triggered by heat greater than 110 degrees Fahrenheit – so the hot chili pepper is indeed aptly named. The ion channel also contributes to the hypersensitivity to heat felt in injured tissue, such as sunburned skin. When tissue is hypersensitive the stimulus is perceived as burning hot within the brain.
“These findings have led us to ask how TRPV1 functions as a molecular integrator of physical and chemical signals that regulate sensory neuron excitability under normal and pathophysiological conditions,” Julius says.
Subsequently, Julius led a successful quest to identify the molecular source of the icy sensation triggered by menthol from mint plants. In the same way that Julius’ lab team earlier demonstrated that heat acts on the ion channel similarly to chili’s capsaicin, they cloned a menthol ion channel from sensory neurons and showed that it also is switched on in response to cold. This ion channel – named TRPM8 – is structurally similar to TRPV1.
Lab Findings Spur Painkiller Drug Research
“We are asking how these ion channels contribute to the detection of heat or cold, and how their activity is modulated in response to tumor growth, infection, or other forms of injury that produce inflammation and pain hypersensitivity,” Julius says.
More recently, Julius and his lab group showed that a third ion channel – TRPA1 – is activated by pungent wasabi and similar mustards. Evidence from their lab suggests that this ion channel plays a key role in the detection of environmental irritants and in the development of chronic pain hypersensitivity. One indication of the importance of this work to medicine is the now intense interest in TRP channels as potential targets for the development of novel analgesic agents.