By Keith Gillogly

Now, researchers at the Jacobs School of Medicine and Biomedical Sciences have received federal funding to study the transient molecular structure and dynamics of a protein receptor that’s critical to pain detection.

Feng Qin, PhD, professor of physiology and biophysics, is principal investigator on a new $2.2 million, four-year grant from the National Institute of General Medical Sciences, part of the National Institutes of Health. The title of his research project is “Mechanisms of Heat Sensing Nociceptive Vanilloid Receptors.”

Qin and his colleagues have long studied the protein receptor TRPV1, found at the endings of peripheral nerves in the skin and integral to detecting temperature and pain.

Ion channels like TRPV1 can detect a variety of physical and chemical stimuli. But the investigators’ previous research suggests that heat itself causes these receptors to become unstable and partially unfold, prompting activation.

These heat-induced structural changes can occur on the millisecond timescale. Yet being able to visualize the changing molecular scaffolding within this extremely brief period could be key to manipulating these receptors and to uncovering the molecular pathways underlying heat-induced activation, Qin says.

“These receptors are critical targets on pain pathways,” Qin says. “Now, the goal is to see what kind of structural changes occur during this activation pathway.”

To do so, the researchers will use a new methodology involving cryo-electron microscopy coupled with very rapid heating and freezing of the TRPV1 protein.

The receptors will be rapidly heated using a laser and then plunge-frozen in liquid ethane at precisely controlled time points, trapping their structural states.

The frozen samples can then be placed under an electron microscope for detailed structural study. In order to follow the dynamic structural changes, the researchers will look at samples frozen at various millisecond intervals.  

Chronic pain affects one in five Americans, yet many don’t find adequate relief from existing treatments, Qin says. Overreliance on opioids prescribed for severe pain has fueled an ongoing crisis.  

But opioids function much differently than potential therapies targeting TRPV1 receptors; many of the effects of opioids occur in the brain and spinal cord, whereas therapies targeting TRPV1-like receptors could potentially function where painful stimuli are first detected in peripheral sensory nerves, making them an attractive target for analgesics. 

“These receptors are on the peripheral,” Qin says. “If you target them, basically you can block the pain at the place where it’s generated.”

Qin and his colleagues have, in many cases, built and developed their research tools. “We had to build everything, including the heating apparatus and the software that drives everything,” he says.

The uniqueness of their methods and tools has, he says, helped him and his lab maintain consistent funding since 1996. And because few methods exist to study such fleeting protein dynamics, his lab’s approach could be shared.

For example, their methods could apply to other proteins with transitory activated states, such as certain neuron transmitter receptors involved in synaptic signaling, Qin says.

These proteins can rapidly transition from an activated state to a desensitized state, making their short-loved activated conformations difficult to capture. Therefore a rapid imaging technique to capture and resolve their activated state could advance understanding of these receptors, among other similar proteins.