Thursday, April 25, 2013

Bitter taste receptors in the most unexpected places

Another in our very irregular series on unexpected biological function.  We've written before about spermatogenesis genes found in the brain, and vision-related opsins found in unseeing sea urchin spines.  Today it's bitter taste receptors in the airways -- and testis, and brain, and immune cells, and gastrointestinal tract.  And they may soon be harnessed for the treatment of asthma.  

More than 300 million people have asthma worldwide, a disease that is estimated to cause 1 in 250 deaths.  Prevalence has spiked in the last three decades, and it's still not clear why, though the hygiene hypothesis, the idea that we're too clean, which provokes our immune system to overreact, has gained traction.

There is a lot of variation in the disease -- some people have asthma with allergies, some with exercise, some with respiratory infections, people react differently to existing therapies, some are able to keep their disease well-controlled and others not, and so on.  Of course many genetic studies of asthma have been done, but to date no definitive genes with large effect have been identified. 

Like most complex diseases, it's likely that 'asthma' encompasses a variety of diseases, with a variety of causal circumstances, and again as with other diseases, this complicates the search for causes, both genetic and environmental, as well as treatments.  "Those of us who treat asthma know that it's very different in each person.  It's almost as if each person is an n of one," physician and asthma researcher Fernando Martinez told The Lancet in 2006, when the journal did a special issue on the disease.  In the same issue, the editors called for an end to the use of the word asthma entirely. 

This is all in line with the idea of personalized medicine, genomic or otherwise.  Treatment tailored to every individual.  But is it possible that all cases of asthma may have one thing in common that a single treatment could correct?

Asthma is characterized by wheeze, which happens when smooth muscle cells in the airways contract, causing narrowing of the airways and subsequent difficulty breathing.  Current therapies include bronchodilators, β2 adrenergic receptor agonists, that act on β2 adrenergic receptors to relax smooth muscle and cause airways to dilate.  They don't work for everyone, however, and can have adverse side effects. 

A paper recently published in PLoS Biology reports that smooth muscle in airways has bitter taste receptors, G-protein-coupled receptors, that trigger a cellular response.
Bitter taste receptors (TAS2Rs), a G-protein-coupled receptor family long thought to be solely expressed in taste buds on the tongue, have recently been detected in airways. Bitter substances can activate TAS2Rs in airway smooth muscle to cause greater bronchodilation than β2 adrenergic receptor agonists, the most commonly used bronchodilators. However, the mechanisms underlying this bronchodilation remain elusive. Here we show that, in resting primary airway smooth muscle cells, bitter tastants activate a TAS2R-dependent signaling pathway that results in an increase in intracellular calcium levels, albeit to a level much lower than that produced by bronchoconstrictors. In bronchoconstricted cells, however, bitter tastants reverse the bronchoconstrictor-induced increase in calcium levels, which leads to the relaxation of smooth muscle cells.
So, the search is on for bitter tastants that would be good candidates for a new and more effective class of bronchodilator.  By addressing a response that is characteristic of all asthma, constriction of the airway, this approach could be a much needed one-size-fits-all kind of drug, with fewer side effects than the current class of bronchodilators.

But why are bitter receptors in these unexpected places?  Olfactory receptors have also been found expressed in some tissues other than the nasal passageways, to the extent that someone once suggested that, in their diversity and uniqueness, they could be used body-wide as a kind of tissue-specific molecular 'area code'.  This doesn't seem likely, as there hasn't been much in that line of evidence for several years.

But these stories do show the diversity of gene functions and uses.  Do bitter taste receptors in the airways mean anything?  Have they got there by chance alone, with no historic nor adaptive function?  Could their presence there be a simple developmental side effect of their needing to be properly expressed in the tongue, which develops in nearby tissues in the embryo?  If so, why are they in the testis, and immune cells, suggesting they have multiple and diverse functions?

We've written many times about roadblocks to understanding. What we think we know too often blinds us to what we don't know.

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