G i-coupled γ-aminobutyric acid-B receptors cross-regulate phospholipase C and calcium in airway smooth muscle

Kentaro Mizuta, Fumiko Mizuta, Dingbang Xu, Eiji Masaki, Reynold A. Panettieri, Charles W. Emala

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system, and exerts its actions via both ionotropic (GABA A) and metabotropic (GABA B) receptors. Although the functional expression of GABA B receptors coupled to the G i protein was reported for airway smooth muscle, the role of GABA B receptors in airway responsiveness remains unclear. We investigated whether G i-coupled GABA B receptors cross-regulate phospholipase C (PLC), an enzyme classically regulated by G q-coupled receptors in human airway smooth muscle cells. Both the GABA B-selective agonist baclofen and the endogenous ligand GABA significantly increased the synthesis of inositol phosphate, whereas GABA A receptor agonists, muscimol, and 4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol exerted no effect. The baclofen-induced synthesis of inositol phosphate and transient increases in [Ca 2+] i were blocked by CGP35348 and CGP55845 (selective GABA B antagonists), pertussis toxin (PTX, which inactivates the G iprotein), gallein (a G βγ signaling inhibitor), U73122 (an inhibitor of PLC-β), and xestospongin C, an inositol 1,4,5-triphosphate receptor blocker. Baclofen also potentiated the bradykinin-induced synthesis of inositol phosphate and transient increases in [Ca 2+] i, which were blocked by CGP35348 or PTX. Moreover, baclofen potentiated the substance P-induced contraction of airway smooth muscle in isolated guinea pig tracheal rings. In conclusion, the stimulation of GABA Breceptors in human airway smooth muscle cells rapidly mobilizes intracellular Ca 2+ stores by the synthesis of inositol phosphate via the activation of PLC-β, which is stimulated by G βγ protein liberated from G iproteins coupled to GABA B receptors. Furthermore, crosstalk between GABA B receptors and G q-coupled receptors potentiates the synthesis of inositol phosphate, transient increases in [Ca 2+] i, and smooth muscle contraction through G i proteins.

Original languageEnglish
Pages (from-to)1232-1238
Number of pages7
JournalAmerican journal of respiratory cell and molecular biology
Volume45
Issue number6
DOIs
Publication statusPublished - 2011 Dec 1

Keywords

  • Airway smooth muscle
  • G
  • G protein
  • Inositol phosphate
  • Phospholipase C

ASJC Scopus subject areas

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

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