GABAAreceptors are expressed and facilitate relaxation in airway smooth muscle

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. GABAAchannels 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 GABAAchannels and GABABreceptors have been functionally identified on peripheral nerves in the lung, GABAAchannels have never been identified on ASM itself. We detected the mRNA encoding of the GABAAα4-, α5-, β3-, 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 GABAAα4-, α5-, β3-, and γ2-subunit proteins in native human and guinea pig ASM and cultured human ASM cells. The GABAAβ3-subunit protein was immunohistochemically localized to ASM in guinea pig tracheal rings. While muscimol, a specific GABAAchannel 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 GABAAchannels 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.