Abstract
Activation of bitter taste receptors (T2Rs) in human airway smooth muscle cells leads to muscle relaxation and bronchodilation. This finding led to our hypothesis that T2Rs are expressed in human pulmonary artery smooth muscle cells and might be involved in regulating the vascular tone. RT-PCR was performed to reveal the expression of T2Rs in human pulmonary artery smooth muscle cells. Of the 25 T2Rs, 21 were expressed in these cells. Functional characterization was done by calcium imaging after stimulating the cells with different bitter agonists. Increased calcium responses were observed with most of the agonists, the largest increase seen for dextromethorphan. Previously in site-directed mutational studies, we have characterized the response of T2R1 to dextromethorphan, therefore, T2R1 was selected for further analysis in this study. Knockdown with T2R1 specific shRNA decreased mRNA levels, protein levels and dextromethorphan-induced calcium responses in pulmonary artery smooth muscle cells by up to 50%. To analyze if T2Rs are involved in regulating the pulmonary vascular tone, ex vivo studies using pulmonary arterial and airway rings were pursued. Myographic studies using porcine pulmonary arterial and airway rings showed that stimulation with dextromethorphan led to contraction of the pulmonary arterial and relaxation of the airway rings. This study shows that dextromethorphan, acting through T2R1, causes vasoconstrictor responses in the pulmonary circuit and relaxation in the airways.
Highlights
Taste perception fulfills an essential role in evaluating the quality and nutritional value of food prior to ingestion
To determine the expression of TAS2R transcripts in hPASMCs, all 25 TAS2Rs were selected for analysis by RT
Transcripts of most of the TAS2Rs were detected in the hPASMCs, except for TAS2R16, TAS2R38, TAS2R40 and TAS2R41 (Figure 1)
Summary
Taste perception fulfills an essential role in evaluating the quality and nutritional value of food prior to ingestion. Humans can taste many compounds but are able to distinguish between five basic tastes, which are bitter, sweet, umami, salt and sour. The signal transduction for sweet, umami and bitter tastes is mediated through G protein-coupled receptors (GPCRs) [1,2]. Bitter taste provides a defense mechanism against the ingestion of toxic substances. Bitter taste is sensed by a family of 25 GPCRs, referred to as T2Rs, which are localized in clusters on chromosomes 5p15, 7q31 and 12p13 [3,4]. The ligands that activate T2Rs have diverse chemical structures and include natural alkaloids, such as quinine, nicotine, and synthetic compounds such as dextromethorphan (DXM)
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