Coupling of airway smooth muscle bitter taste receptors to intracellular signaling and relaxation is via Gαi1,2,3

Donghwa Kim, Jung A. Woo, Ezekiel Geffken, Steven S. An, Stephen B. Liggett

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Bitter taste receptors (TAS2Rs) are expressed on human airway smooth muscle (HASM) and evoke marked relaxation. Agonist interaction with TAS2Rs activates phospholipase C and increases compartmentalized intracellular Ca2+([Ca2+]i) via inositol 1,4,5 triphosphate. In taste cells, theGprotein gustducin couples TAS2R to phospholipase C; however, we find very low levels ofGagustmRNAor protein in HASM.Wehypothesized that anotherGprotein inHASM transmits TAS2R function. TAS2R signaling to [Ca2+]i, extracellular signal-regulated kinase (ERK) 1/2, and physiologic relaxation was sensitive to pertussis toxin, confirming a role for a member of the Gi family. a subunit expression in HASM was Gαi2.Gαi1=Gαi3. Gαtrans1≈Gatrans2, with Gagust and Gao at the limits of detection (.100-fold lower than Gai2). Small interfering RNA knockdowns in HASM showed losses of [Ca21]i and ERK1/2 signaling when Gai3, Gai2, orGai3 were reduced. Gαtrans1 and Gatrans2 knockdowns had no effect on [Ca21]i and a minimal, transient effect on ERK1/2 phosphorylation. Furthermore, Gαgust and Gαoknockdowns did not affect any TAS2R signaling. In overexpression experiments in human embryonic kidney-293T cells, we confirmed an agonistdependent physical interaction between TAS2R14 and Gai2. ASM cells from transgenic mice expressing a peptide inhibitor ofGαi2 had attenuated relaxation to TAS2R agonist. These data indicate that, unlike in taste cells, TAS2Rs couple to the prevalent G proteins, Gαi1, Gαi2, and Gai3, with no evidence for functional coupling to Gαgust. This absence of function for the "canonical" TAS2R G protein in HASM may be due to the very low expression of Gagust, indicating that TAS2Rs can optionally couple to several G proteins in a cell type-dependent manner contingent upon G protein expression.

Original languageEnglish (US)
Pages (from-to)762-771
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume56
Issue number6
DOIs
StatePublished - Jun 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Keywords

  • Airway smooth muscle
  • Asthma
  • Bitter taste receptors
  • Chronic obstructive pulmonary disease
  • G proteins

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