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Single-Nucleotide Polymorphisms of TAS2R46 Affect the Receptor Downstream Calcium Regulation in Histamine-Challenged

Giulia Lecchi1, Chiara Mocchetti1, Davide Tunesi1

  • 1Department of Health Sciences, School of Medicine, University of Piemonte Orientale, Via Solaroli, 17, 28100 Novara, Italy.

Cells
|July 26, 2024
PubMed
Summary

Bitter taste receptors (TAS2Rs) in airways play a role in bronchodilation. Specific genetic variations (SNPs) in TAS2R46, particularly in the fourth transmembrane domain, critically impact receptor function and mitochondrial calcium uptake.

Keywords:
SNPsTAS2Rbitter taste receptorcalcium signallingpolymorphism

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Physiology

Background:

  • Bitter taste receptors (TAS2Rs) are present in extraoral tissues, forming a whole-body sensory system with potential therapeutic implications.
  • TAS2R46 activation in airway smooth muscle cells promotes bronchodilation via mitochondrial calcium uptake.
  • Genetic variations, specifically single nucleotide polymorphisms (SNPs), have been identified in the TAS2R46 gene sequence.

Purpose of the Study:

  • To investigate the structure-function relationship of TAS2Rs, focusing on the impact of common SNPs on TAS2R46 activity.
  • To evaluate how specific SNPs in TAS2R46 influence calcium signaling pathways.
  • To correlate structural mutations with functional changes in TAS2R46 receptor activity.

Main Methods:

  • Generation of a cellular model expressing native TAS2R46.
  • Activation of TAS2R46 with its ligand, absinthin, to measure calcium fluxes.
  • Site-directed mutagenesis to introduce common SNPs into TAS2R46.
  • In silico docking studies to analyze structural changes and their effects.

Main Results:

  • Four common SNPs in TAS2R46 were analyzed for their effects on calcium signaling.
  • SNPs located in different transmembrane domains exhibited varying impacts on the TAS2R46 signal cascade.
  • A specific SNP in the fourth transmembrane domain abolished mitochondrial calcium uptake, while one in the sixth domain had no effect.

Conclusions:

  • The fourth transmembrane domain of TAS2R46 is crucial for its intrinsic receptor activity.
  • SNPs within the fourth transmembrane domain significantly disrupt TAS2R46-mediated mitochondrial calcium uptake and bronchodilation.
  • Understanding SNP-driven functional changes in TAS2R46 offers insights into personalized medicine approaches for respiratory conditions.