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A Sixth Sense, and Beyond

April 2007--Hearing, sight, smell, taste and touch. Growing up, we all learned about the five tools we use to perceive the outside world. While this pentad clearly plays a principal part in processing the abundance of stimuli surrounding us, it’s not the whole story. We also rely on senses that detect more subtle changes, and within the IBBS Center for Sensory Biology, Hopkins researchers are deciphering these less renowned, but no less vital, systems. 

One such system resides in the retina, behind the rods and cones that enable us to see in vivid color by day and find the bathroom at night. There, neurons known as ganglion cells connect the eyes to the brain. While most ganglion cells link to the centers of image-forming vision, a small subset travels to the hypothalamus—the center of our circadian clock.

For years, scientists believed that the hypothalamus processed light information from the rods and cones to reset the clock as needed, as when we adjust to new time zones. “The intriguing thing about that,” says neuroscience professor King-Wai Yau, “is that some blind people can still overcome jetlag.”  

To solve this circadian mystery, Yau, along with former postdoc and now Hopkins professor Samer Hattar and student Hsi-Wen “Rock” Liao, poked around mouse retinal ganglion cells and found that about 1 percent contain melanopsin, a pigment that enables these cells to absorb light just like rods and cones. These photosensitive ganglion cells are the same subset that connects to the brain regions not involved in image-forming vision.

Like a light meter on photography equipment, Yau notes, photosensitive ganglion cells relay the amount of ambient light to the brain so it can sync up our internal clock when we fly to Europe, for example, or constrict the aperture of our pupils in response to bright light.  

Both Yau and Hattar continue to study these photosensitive ganglion cells to better understand how they develop, how they work and how they evolved. “Evolutionarily, these cells are more similar to most photoreceptors in lower animals than to our own rods and cones,” says Yau.

The resemblance, he notes, arises from the fact that the photosensitive ganglion cells appear to convert light energy to nerve signals by means of a cellular signaling pathway more akin to that found in lower animals. It has also been suggested that these cells may function through proteins known as TRP channels, gates on the plasma membrane that, in lower animals such as flies, open up when triggered by light and let in a wave of sodium and calcium ions. Regular vision operates on a different signaling pathway, using protein gates called cyclic-nucleotide-gated ion channels.

Fellow sensory scientist Michael Caterina knows all about TRP channels, as they play a pivotal role in his studies of heat sensation. When we transition from the comforts of an air-conditioned house to a sweltering summer day, specialized nerves in our skin report this change to the brain. They do so with the help of temperature-responsive TRP channels that act as tiny molecular thermometers. “We have a whole series of TRP temperature sensors, each calibrated to open at a different temperature,” Caterina says, “ranging from bitter cold to fiery hot.”

Caterina has been exploring how these thermosensors relate to classical pain/touch receptors; one TRP channel that responds to extreme heat (above 42 C) also responds to capsaicin, the chemical that gives chili peppers their “kick” (and explains why spicy foods are associated with burning).

“Some of these sensory nerves are pulling double duty by sensing both heat and pain,” Caterina says, “but we also find some segregation.” For example, most pain nerves activate regions of the brain that direct us to pull our hands away from a hot stovetop, but other heat- and cold-sensitive nerves send signals to the hypothalamus, which processes these temperature readings to adjust subconscious heat responses like sweating.

Caterina has also found that some skin cells, not the nerves intermingled with them, contain heat channels triggered to respond to modest temperature increases (between 30 and 40 C). “We think of our skin as just a physical barrier to the outside world, but now it seems that it might also be a first-line responder to encroaching heat,” he says, “warning us that things are about to get uncomfortable.”

The parallel themes permeating Caterina’s and Yau’s work apply to most sensory systems, notes Craig Montell, who discovered the first TRP channel in fruit flies many years ago. “Back then, I didn’t think that one protein would explode into a whole field,” he says. “But we now know that these channels exist in animals from worms to people and are involved in every sense. And this use of similar ion channels is just one example of the intriguing similarities underlying the different senses.”

--Nick Zagorski

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