Submitted on July 23, 2007
Accepted on April 3, 2008
GABAA receptors are expressed and facilitate relaxation in airway smooth muscle
Kentaro Mizuta1, Dingbang Xu1, Yaping Pan2, George Comas3, Joshua R Sonett3, Yi Zhang1, Reynold A Panettieri, Jr4, Jay Yang1, and Charles W. Emala, Sr1*
1 Anesthesiology, Columbia University, New York, New York, United States
2 Physiology and Cellular Biophysics, Columbia University, New York, New York, United States
3 Surgery, Columbia University, New York, New York, United States
4 Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, United States; , United States
* To whom correspondence should be addressed. E-mail: cwe5{at}columbia.edu.
-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian CNS 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 
4, 5, 
3, 
, 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 GABAA 4, 5, 3 and 2 subunit proteins in native human and guinea pig ASM and cultured human ASM cells. The GABAA 3 subunit protein was immunohistochemically localized to ASM in guinea pig tracheal rings. While muscimol, a specific GABAA channel agonist, did not effect 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.
