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PLoS One. 2016 May 25;11(5):e0156347. doi: 10.1371/journal.pone.0156347. eCollection 2016.

The Pharmacochaperone Activity of Quinine on Bitter Taste Receptors.

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Department of Oral Biology, and Manitoba Chemosensory Biology (MCSB) Research group, University of Manitoba, Winnipeg, MB, R3E 0W2, Canada.
Children's Hospital Research Institute of Manitoba, Winnipeg, MB, R3E 3P4, Canada.


Bitter taste is one of the five basic taste sensations which is mediated by 25 bitter taste receptors (T2Rs) in humans. The mechanism of bitter taste signal transduction is not yet elucidated. The cellular processes underlying T2R desensitization including receptor internalization, trafficking and degradation are yet to be studied. Here, using a combination of molecular and pharmacological techniques we show that T2R4 is not internalized upon agonist treatment. Pretreatment with bitter agonist quinine led to a reduction in subsequent quinine-mediated calcium responses to 35 ± 5% compared to the control untreated cells. Interestingly, treatment with different bitter agonists did not cause internalization of T2R4. Instead, quinine treatment led to a 2-fold increase in T2R4 cell surface expression which was sensitive to Brefeldin A, suggesting a novel pharmacochaperone activity of quinine. This phenomenon of chaperone activity of quinine was also observed for T2R7, T2R10, T2R39 and T2R46. Our results suggest that the observed action of quinine for these T2Rs is independent of its agonist activity. This study provides novel insights into the pharmacochaperone activity of quinine and possible mechanism of T2R desensitization, which is of fundamental importance in understanding the mechanism of bitter taste signal transduction.

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