gamma-aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes

gamma-Hydroxybutyrate (GHB). an anesthetic adjuvant analog of gamma-aminobu tyrate (GABA), depresses cell excitability in hippocampal neurons by induci ng hyperpolarization through the activation of a prominent inwardly rectify ing K+ (Kir3) conductance. These GABA type B (GABA(B))-like effects are cle arly shown at high concentrations of GHB corresponding to blood levels usua lly reached during anesthesia and are mimicked by the GABA(B) agonist baclo fen. Recent studies of native GABA(B) receptors (GABA(B)Rs) have favored th e concept that GHB is also a selective agonist. Furthermore, cloning has de monstrated that GABA(B)Rs assemble heteromeric complexes from the GABA(B)R1 and GABA(B)R2 subtypes and that these assemblies are activated by GHB. The surprisingly high tissue content, together with anti-ischemic and protecti ve 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 p rovide electrophysiological evidence that GHB activates an inwardly rectify ing K+ current in rat ventricular myocytes. This effect is mimicked by bacl ofen. reversibly inhibited by GABA(B) antagonists, and prevented by pertuss is toxin pretreatment. Both GABA(B)R1 and GABA(B)R2 are detected in cardiom yocytes by Western blotting and are shown to coimmunoprecipitate. Laser sca nning confocal microscopy discloses an even distribution of the two recepto rs in the sarcolemma and along the transverse tubular system. Hence. we con clude that GABA(B)Rs are distributed not only in neuronal tissues but also in the heart, where they can be activated and induce electrophysiological a lterations through G-protein-coupled inward rectifier potassium channels.