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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/L1206    most recent 00287.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Mizuta, K. Articles by Emala, C. W. PubMed PubMed Citation Articles by Mizuta, K. Articles by Emala, C. W., Sr.

GABA_A receptors are expressed and facilitate relaxation in airway smooth muscle

Departments of ¹Anesthesiology, ²Physiology and Cellular Biophysics, and ³Surgery, College of Physicians and Surgeons of Columbia University, New York, New York; and ⁴Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Submitted 23 July 2007 ; accepted in final form 3 April 2008

-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system and exerts its actions via both ionotropic (GABA_A) channels and metabotropic (GABA_B) receptors. GABA_A 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 GABA_A channels and GABA_B receptors have been functionally identified on peripheral nerves in the lung, GABA_A channels have never been identified on ASM itself. We detected the mRNA encoding of the GABA_{A 4}-, ₅-, β₃-, -, _1–3-, -, and -subunits in total RNA isolated from native human and guinea pig ASM and from cultured human ASM cells. Selected immunoblots identified the GABA_{A 4}-, ₅-, β₃-, and ₂-subunit proteins in native human and guinea pig ASM and cultured human ASM cells. The GABA_A β₃-subunit protein was immunohistochemically localized to ASM in guinea pig tracheal rings. While muscimol, a specific GABA_A 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 GABA_A-selective antagonist gabazine. Muscimol also relaxed a contraction induced by an alternative contractile agonist histamine. These results demonstrate that functional GABA_A 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.

RT-PCR; immunoblot; tachykinin; guinea pig; organ bath; histamine