New mechanism for relaxing airways using bitter tasting substances

(Press-News.org) A team of scientists at the University of Massachusetts Medical School have found that substances which give some foods their bitter flavors can also act to reverse the contraction of airway cells. This reversal, known as bronchodilation, is needed to treat airway obstructive diseases such as asthma and chronic obstructive pulmonary disease. The new findings, which could have significant implications for such treatments, are published March 5 in the open access journal PLOS Biology.

The sense of taste is mediated by taste receptor cells bundled in our taste buds. These receptors were thought to only exist in the tongue, but recent discoveries have shown that they are actually expressed in various cell types throughout the body. In particular, bitter taste receptors exist in smooth muscle cells in the airway, acting to relax the cells when exposed to bitter-tasting substances.

A hallmark of an asthma attack is excessive contraction of these smooth muscle cells, which causes narrowing of the airways and breathing difficulties. The fact that bitter substances can relax these smooth muscle cells suggests that they may have the potential to halt asthma attacks, and in fact could even be an improvement over current treatments since the relaxation effects are quite fast. Indeed, experiments in mice suggest that the effects are stronger.

However, the mechanisms through which bitter taste receptor activation leads to cell relaxation were unknown. To help unravel these mechanisms, Dr. Ronghua ZhuGe and his colleagues examined the effect of bitter substances on the contraction of airways and in single isolated cells.

During an asthma attack, membrane channels on smooth muscle cells in the airways are opened, allowing calcium to flow into the cell and causing the cell to contract. This leads to the airways becoming narrower, and making breathing more difficult. Dr. ZhuGe and colleagues determined that bitter substances shut down these calcium channels, allowing bronchodilation.

Bitter taste receptors, like most receptors, span the plasma membrane of the cell. Part of the receptor is outside the cell, able to bind to (and hence "sense") bitter substances outside the cell. When a bitter compound binds to a bitter taste receptor, the receptor releases a G-protein, which then splits into two parts: a G alpha subunit and G beta-gamma dimer. "It is the G beta-gamma dimer that likely acts to close the calcium channels on the plasma membrane," explained Kevin Fogarty, director of the Biomedical Imaging Group in the Program in Molecular Medicine at UMMS, and a co-author of the study. "Once the channels are closed, the calcium level returns to normal and the cell relaxes," he said. "This ends the asthma attack."

"With this new understanding of how bitter substances are able to relax airways, we can focus our attention on studying these receptors and on finding even more potent bitter compounds with the potential to be used therapeutically to end asthma attacks," said Dr. ZhuGe.

### Funding: The study was supported by NIH grant RO1 HL73875 to Ronghua ZhuGe. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Citation: Zhang C-H, Lifshitz LM, Uy KF, Ikebe M, Fogarty KE, et al. (2013) The Cellular and Molecular Basis of Bitter Tastant-Induced Bronchodilation. PLOS Biol 11(3): e1001501. doi:10.1371/journal.pbio.1001501

CONTACT: Jim Fessenden
UMass Medical School Communications
Tel: 508-856-2000
james.fessenden@umassmed.edu END