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Updated: Mar 20, 2026
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Published on: August 17, 2018
The Pharmacochaperone Activity of Quinine on Bitter Taste Receptors
Jasbir D Upadhyaya1,2, Raja Chakraborty1,2, Feroz A Shaik1,2
1Department of Oral Biology, and Manitoba Chemosensory Biology (MCSB) Research group, University of Manitoba, Winnipeg, MB, R3E 0W2, Canada.
Abstract:
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.
Insights
Quinine, a bitter taste agonist, does not internalize bitter taste receptors (T2Rs). Instead, it increases T2R cell surface expression, revealing a novel pharmacochaperone activity crucial for understanding bitter taste desensitization.
Area of Science:
- Taste receptor research
- Molecular pharmacology
- Cellular signaling
Background:
- Bitter taste perception is mediated by 25 human bitter taste receptors (T2Rs).
- Mechanisms of bitter taste signal transduction and T2R desensitization remain largely unknown.
- Cellular processes like receptor internalization, trafficking, and degradation in T2R desensitization require further investigation.
Purpose of the Study:
- To investigate the cellular mechanisms underlying T2R desensitization.
- To explore the effects of bitter agonists, specifically quinine, on T2R4 behavior.
- To identify novel functions of quinine beyond its agonist activity.
Main Methods:
- Utilized a combination of molecular and pharmacological techniques.
- Assessed T2R4 internalization and cell surface expression upon agonist treatment.
- Measured quinine-mediated calcium responses and Brefeldin A sensitivity.
Main Results:
- T2R4 was not internalized following treatment with bitter agonists.
- Quinine pretreatment reduced subsequent quinine-mediated calcium responses by 35 ± 5%.
- Quinine treatment increased T2R4 cell surface expression, suggesting pharmacochaperone activity, which was also observed for T2Rs 7, 10, 39, and 46.
Conclusions:
- Bitter taste receptor (T2R) desensitization may involve mechanisms other than internalization.
- Quinine exhibits novel pharmacochaperone activity on T2Rs, independent of its agonist function.
- This discovery offers new insights into bitter taste signal transduction and T2R regulation.
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