GABAA receptors are expressed and facilitate relaxation in airway smooth muscle

Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jay Yang, Charles W. Emala

Research output: Contribution to journalArticlepeer-review

65 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 (GABAA) channels and metabotropic (GABAB) receptors. GABAA channels are ubiquitously expressed in neuronal tissues, and in mature neurons modulate an inward chloride current resulting in neuronal inhibition due to membrane hyperpolarization. In airway smooth muscle (ASM) cells, membrane hyperpolarization favors smooth muscle relaxation. Although GABAA channels and GABAB receptors have been functionally identified on peripheral nerves in the lung, GABAA channels have never been identified on ASM itself. We detected the mRNA encoding of the GABAA α4-, α5-, α3-, δ-, γ1-3-, π-, and θ-subunits in total RNA isolated from native human and guinea pig ASM and from cultured human ASM cells. Selected immunoblots identified the GABA A α4-, α5-, β3-, and γ2-subunit proteins in native human and guinea pig ASM and cultured human ASM cells. The GABAA β3-subunit protein was immunohistochemically localized to ASM in guinea pig tracheal rings. While muscimol, a specific GABAA channel agonist, did not affect the magnitude or the time to peak contractile effect of substance P, it directly concentration dependently relaxed a tachykinin-induced contraction in guinea pig tracheal rings, which was inhibited by the GABAA-selective antagonist gabazine. Muscimol also relaxed a contraction induced by an alternative contractile agonist histamine. These results demonstrate that functional GABAA channels are expressed on ASM and suggest a novel therapeutic target for the relaxation of ASM in diseases such as asthma and chronic obstructive lung disease.

Original languageEnglish
Pages (from-to)L1206-L1216
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume294
Issue number6
DOIs
Publication statusPublished - 2008 Jun
Externally publishedYes

Keywords

  • Guinea pig
  • Histamine
  • Immunoblot
  • Organ bath
  • RT-PCR
  • Tachykinin

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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