An itch you just can’t scratch

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diagram of proteins binding to receptors causing itch
The proteins that make you itch
Scientists discovered how a pair of proteins work together to produce chronic itch. Courtesy of Bautista Lab, UC Berkeley Department of Molecular and Cell Biology.

NIH-funded study identifies proteins that may cause chronic itch

Everyone knows the best way to suppress an itch is to scratch it, but for people who suffer from skin diseases like eczema, no amount of scratching can bring relief. Fortunately, help may be on the way. Scientists from the Buck Institute for Research on Aging and the University of California, Berkeley have identified a pair of proteins responsible for chronic itching. The study, published in Neuron and partially funded by the NIH’s National Institute of Neurological Disorders and Stroke (NINDS), may lead to treatments that can stop an itch at its source.

“It’s thought that 1 in 10 people will suffer from chronic itch at some point in their lifetime,” said co-senior author Diana Bautista, Ph.D., an associate professor in the Department of Molecular and Cell Biology at UC Berkeley. “Unlike the itch associated with a mosquito bite, chronic itch is incredibly debilitating and there are very few therapies available, so it’s a really important unmet clinical problem.”

Scientists have long known that high levels of serotonin in the skin cause persistent itching, but Dr. Bautista’s team is the first to discover why. Many neurons have proteins on their surfaces called receptors that serve as binding sites for specific chemicals. These interactions cause the neuron’s ion channels to open, which in turn influences the flow of ions into and out of the neuron and alters its activity. The team learned that when serotonin binds to a receptor called HTR7 in skin sensory neurons, it leads to the opening of an ion channel called TRPA1. This increases the neurons’ firing rates and triggers the sensation of itch.

“For neurons to become excited, you need a receptor to communicate with an ion channel,” said Dr. Bautista. “We tried a variety of experiments and found that HTR7 communicates with the TRPA1 ion channel. Both receptors seem to be working together to mediate chronic itch.” 

The researchers began their study by injecting genetically distinct mice with itch-inducing compounds and noted that this produced widely varying periods of scratching among the animals. The team thought this might be due to differences in gene expression – the extent to which a gene is active – in sensory neurons in the mice’s skin.

“Not all mice scratched to the same extent even though they were treated exactly the same,” said Rachel Brem, Ph.D., the study’s other senior author and an associate professor at the Buck Institute. “We looked for genes whose expression went up and down in a manner that paralleled itch itself.”

The researchers found more than 70 genes whose expression was higher in the more itch-sensitive mice. Of these, the gene for the HTR7 receptor was the most closely linked to itch. In fact, the HTR7 gene was twice as active in the itchiest mice compared to the least sensitive mice.  

“Seeing HTR7 as one of those genes that were most correlated with itch behavior got us really excited,” said Dr. Bautista.

To further examine the relationship between HTR7, TRPA1 and itch, the scientists examined how molecules that bind to the HTR7 receptor affect neurons and mice lacking one or both of those proteins. These experiments revealed that those chemicals had no effect on neurons lacking TRPA1 and didn’t produce scratching behavior in mice missing either protein. Similarly, the antidepressant medication Zoloft, a selective serotonin reuptake inhibitor (SSRI) that raises serotonin levels in the skin, increased scratching much more in genetically normal mice than mice without HTR7 or TRPA1. This suggests that both proteins are needed for serotonin to produce itching and also explains why 2 to 4 percent of people taking SSRIs experience itching or rash as a side effect.

The researchers confirmed their theory in mice with an eczema-like chronic itch condition. As in human eczema, the mice’s skin contained high levels of serotonin. However, mice without HTR7 or TRPA1 showed less severe skin damage and scratched much less than control mice, despite the fact that the serotonin levels in their skin were the same.

“Having some additional drug targets like HTR7 or TRPA1 to treat eczema and other forms of chronic itch could be a new avenue for further research,” said Dr. Bautista, who believes those genes could serve as useful targets for new drug development.

This work was supported by grants from NINDS (NS084812, NS 040538, NS 077224, and NS 063307) and National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR059385).

– by Brandon Levy

References:

Morita et al. “HTR7 Mediates Serotonergic Acute and Chronic Itch,” Neuron, June 11, 2015. DOI: 10.1016/j.neuron.2015.05.044.

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The NINDS (http://www.ninds.nih.gov) is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (http://www.niams.nih.gov/) is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.