Focal Paper by Chenghai Zhang et al
Title of paper done by interviewee: Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction- by Deshpande et al
Sufferers of respiratory ailments such as asthma, COPD, and emphysema are prone to airway smooth muscle (ASM) constriction, which results in difficulty breathing. These muscle contractions take place as a result of a trigger in the release of Ca2+ ions brought about via a stimulated response from parasympathetic nervous system. As a result, numerous treatments have been discovered to facilitate the process of bronchodilation, to relax ASM. The most commonly used bronchodilators are β2 agonists, which act on the ADRB2 receptor in ASM, a receptor which, when its genes are mutated, can result in asthma. β2 agonists stimulate an increase in levels of the second messenger cyclic adenosine monophosphate (cAMP) to decrease the outflow of Ca2+ from the muscle cells in the airway of the respiratory system. However, these β2 agonists come with various side effects, including muscle tremors and even heart palpitations in some patients.
Work in 2010 by Dr. Deepak Deshpande et al introduced the previously unknown fact that bitter-taste receptors known as TAS2Rs were found in airway smooth muscle. After experimentation with bitter tastants such as saccharin and chloroquine, it was observed that these bitter-tastants could induce relaxation of mouse ASM cells. (Deshpande, 2010) From this, the concept of bitter tastant-induced bronchodilation was brought forward. There lay the possibility that bitter tastants could be used to treat bronchoconstriction in respiratory patients, which had hitherto never been heard of before. He observed an unexpected increase in Ca2+ ions as a result of bitter tastant application, a phenomenon with which he attributed the relaxation of the ASM cells. (Deshpande, 2010) However, in 2013, Chenghai Zhang et al, chose to delve further in this line of research which was still relatively unexplored. After experimentation with mouse ASM cells subject to contraction, Chenghai Zhang et al proved that bitter tastants could, in fact, induce bronchodilation, but via an opposite mechanism: a bitter tastant-induced decrease of Ca2+ production via inhibition of L-type voltage-dependent calcium channels during bronchoconstriction. (Zhang et al, 2013)While the paper by Zhang et al was the focal paper of the project, the authors were unavailable for an interview. Instead, Dr. Deepak Deshpande, one of the pioneers of this new discovery, was interviewed. Dr. Deshpande indicated that his eventual choice of work on airway smooth muscle manifested from his background in veterinary medicine, a background which stemmed from a genuine interest in anatomy and animals from a very young age. This was first done at the University of Agricultural Sciences in Bengaluru, India, from where he originally hails. Dr. Deshpande is currently an assistant professor of pharmacology at the University of Maryland, Baltimore.
Dr. Deshpande claimed that the discovery of bitter-taste receptors (TAS2Rs) was an “accidental one”. He initially planned to carry out a microarray to examine gene expression from RNA in airway smooth muscle, only to be surprised by observing the expression associated with TAS2Rs. Deshpande cites the period in which this experiment was carried out as “a period of pure surprise”. After discovering these TAS2Rs, he decided to test their functionality via addition of bitter-tastants, and unexpectedly, the ASM started relaxing. His conclusion that bitter tastant-induced Ca2+ increase was the reason for the ASM relaxation was one which he “reluctantly accepted” after numerous tests to determine whether or not this was just an “unrepeatable incident”. Deshpande was perplexed by the results, claiming he had to reluctantly “ignored the model of muscle contraction”, a model which indicates the increase of Ca2+ to facilitate muscle contraction, not muscle relaxation.
Deshpande’s idea of bitter tastant-induced bronchodilation was proven in the focal paper, but his mechanism for why it did so turned out to be disproven by Zhang et al. Deshpande accepts this, realizing that the increase in Ca2+ which he observed in his experiment was under periods of ASM rest, not under the simulated conditions of ASM contraction. In spite of this, Deshpande spoke of showing pride that he provided a “springboard for a potentially revolutionary concept in respiratory treatment”. Deshpande is a strong advocate for bitter tastant bronchodilation to be applied in the medical field, as “millions of patients around the world cannot afford many expensive asthma medications”, and that this provides a “great chance of decreasing mortality rates from asthma, COPD and emphysema”.
To conclude, the idea of bitter tastant-induced bronchodilation was put forth by Deshpande in 2010 after his unexpected discovery of bitter taste receptors in airway smooth muscle cells. While his proposed mechanism was incorrect, he proved that bitter tastants could induce ASM relaxation, which is applicable in the treatment of bronchoconstriction associated with respiratory ailments such as asthma and COPD. This is a science which is still very much in its early stages, and it has not yet been implemented in the medical field. Nevertheless, Deshpande is optimistic, with the view that “there lies an endless supply of natural and synthesized tastants with which to treat even more patients suffering from respiratory diseases”, and that “sooner rather than later, [bitter tastants] will render β2 agonists obsolete”.