γ-Aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes

Abstract

γ-Hydroxybutyrate (GHB), an anesthetic adjuvant analog of γ-aminobutyrate (GABA), depresses cell excitability in hippocampal neurons by inducing hyperpolarization through the activation of a prominent inwardly rectifying K⁺ (Kir3) conductance. These GABA type B (GABA_B)-like effects are clearly shown at high concentrations of GHB corresponding to blood levels usually reached during anesthesia and are mimicked by the GABA_B agonist baclofen. Recent studies of native GABA_B receptors (GABA_BRs) have favored the concept that GHB is also a selective agonist. Furthermore, cloning has demonstrated that GABA_BRs assemble heteromeric complexes from the GABA_BR1 and GABA_BR2 subtypes and that these assemblies are activated by GHB. The surprisingly high tissue content, together with anti-ischemic and protective effects of GHB in the heart, raises the question of a possible influence of GABA_B agonists on excitable cardiac cells. In the present study, we provide electrophysiological evidence that GHB activates an inwardly rectifying K⁺ current in rat ventricular myocytes. This effect is mimicked by baclofen, reversibly inhibited by GABA_B antagonists, and prevented by pertussis toxin pretreatment. Both GABA_BR1 and GABA_BR2 are detected in cardiomyocytes by Western blotting and are shown to coimmunoprecipitate. Laser scanning confocal microscopy discloses an even distribution of the two receptors in the sarcolemma and along the transverse tubular system. Hence, we conclude that GABA_BRs are distributed not only in neuronal tissues but also in the heart, where they can be activated and induce electrophysiological alterations through G-protein-coupled inward rectifier potassium channels.