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1 Anesthesiology, Columbia University, New York, New York, United States
2 Surgery, Columbia University, New York, New York, United States
3 Medicine, Columbia University, New York, New York, United States
4 Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, 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/GABAC) and metabotropic (GABAB) receptors (R). In addition to their location on neurons, GABA and functional GABAB receptors have been detected in non-neuronal cells in peripheral tissue. Although the GABABR has been shown to function as a pre-junctional inhibitory receptor on parasympathetic nerves in the lung, the expression and functional coupling of GABAB receptors to Gi in airway smooth muscle itself has never been described.
We detected the mRNA encoding multiple splice variants of the GABABR1 and GABABR2 in total RNA isolated from native human and guinea pig airway smooth muscle and from RNA isolated from cultured human airway smooth muscle cells. Immunoblots identified the GABABR1 and GABABR2 proteins in human native and cultured airway smooth muscle. The GABABR1 protein was immunohistochemically localized to airway smooth muscle in guinea pig tracheal rings. Baclofen, a GABABR agonist, elicited a concentration-dependent stimulation of [35S]-GTPS binding in human airway smooth muscle homogenates that was abrogated by the GABABR antagonist, CGP35348. Baclofen also inhibited adenylyl cyclase activity and induced ERK phosphorylation in human airway smooth muscle. Another GABABR agonist, SKF97541, mimicked while pertussis toxin blocked baclofens effect on ERK phosphorylation, implicating Gi protein coupling. Functional GABAB receptors are expressed in human airway smooth muscle. GABA may modulate an uncharacterized signaling cascade via GABAB receptors coupled to the Gi protein in airway smooth muscle.
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