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

Abstract

␥-Hydroxybutyrate (GHB), an anesthetic adjuvant analog of ␥-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 (GABAB)-like effects are clearly shown at high concentrations of GHB corresponding to blood levels usually reached during anesthesia and are mimicked by the GABAB agonist baclofen. Recent studies of native GABAB receptors (GABABRs) have favored the concept that GHB is also a selective agonist. Furthermore, cloning has demonstrated that GABABRs assemble heteromeric complexes from the GABABR1 and GABABR2 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 GABAB 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 GABAB antagonists, and prevented by pertussis toxin pretreatment. Both GABA BR1 and GABABR2 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 GABABRs 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.

Molecular Structure and Physiological Functions of GABABReceptors

“…As in neurons, both GHB (see sect. IIIB2) and baclofen activate an inwardly rectifying K ϩ channel in rat cardiomyocytes (199). GABA B(1) and GABA B(2) expression in cardiomyocytes was confirmed by immunoblotting and in coimmunoprecipitation studies.…”

Functional Expression of GABAB Receptors in Airway Epithelium

“…Several studies indicate the possible expression of functional GABA B receptors in peripheral and nonneuronal cells such as pancreatic b cells (16), adrenocortical cells (17), cardiomyocytes (18), chondrocytes (19), and osteoblasts (20). Furthermore, GABA B R1 mRNA expression was detectable using RT-PCR analysis in many peripheral organs, including heart, spleen, lung, liver, intestine, kidney, stomach, adrenal gland, testis, ovary, and urinary bladder (21).…”

Identification of GABABR2 in Rat Testis and Sperm

“…The staining pattern on the surface of the sperm head with anti-GABABR2 antibody resembled the distribution reported previously with anti-GABABR1 antibody [18], indicating possible congruent localization of both receptors on the head of rat sperm. Lorente et al [23] reported that functional GABABR is composed of both GABABR1 and GABABR2 and is present in rat cardiomyocytes. This finding combined with our present results indicates hat the GABA B R2 subunit occurs in rat testis, sperm and other tissues and is not restricted to the CNS.…”