Functional expression of the GABA_B receptor in human airway smooth muscle

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system and exerts its actions via both ionotropic (GABA_A/GABA_C) and metabotropic (GABA _B) receptors (R). In addition to their location on neurons, GABA and functional GABA_B receptors have been detected in nonneuronal cells in peripheral tissue. Although the GABA_BR has been shown to function as a prejunctional inhibitory receptor on parasympathetic nerves in the lung, the expression and functional coupling of GABA_B receptors to G _i in airway smooth muscle itself have never been described. We detected the mRNA encoding multiple-splice variants of the GABA_BR1 and GABA_BR2 in total RNA isolated from native human and guinea pig airway smooth muscle and from RNA isolated from cultured human airway smooth muscle (HASM) cells. Immunoblots identified the GABA_BR1 and GABA _BR2 proteins in human native and cultured airway smooth muscle. The GABA_BR1 protein was immunohistochemically localized to airway smooth muscle in guinea pig tracheal rings. Baclofen, a GABA_BR agonist, elicited a concentration-dependent stimulation of [³⁵S]GTPγS binding in HASM homogenates that was abrogated by the GABA_BR antagonist CGP-35348. Baclofen also inhibited adenylyl cyclase activity and induced ERK phosphorylation in HASM. Another GABA_BR agonist, SKF-97541, mimicked while pertussis toxin blocked baclofen's effect on ERK phosphorylation, implicating G_i protein coupling. Functional GABA_B receptors are expressed in HASM. GABA may modulate an uncharacterized signaling cascade via GABA_B receptors coupled to the G_i protein in airway smooth muscle.