gamma-aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes.
gamma-Hydroxybutyrate (GHB), an anesthetic adjuvant analog of gamma-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(B)Rs) have favored the concept that GHB is also a selective agonist. Furthermore, cloning has demonstrated 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 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(B)R1 and GABA(B)R2 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(B)Rs 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.
Lorente
P
P
U 390 Institut National de la Santé et de la Recherche Médicale, Instìtut Fédératif de Recherche No. 3, Centre Hospitalier Universitaire Arnaud de Villeneuve, F-34295 Montpellier, France. paco@montp.inserm.fr
Lacampagne
A
A
Pouzeratte
Y
Y
Richards
S
S
Malitschek
B
B
Kuhn
R
R
Bettler
B
B
Vassort
G
G
D000759:Adjuvants, Anesthesia / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002478:Cells, Cultured; D004594:Electrophysiology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D015870:Gene Expression; D006352:Heart Ventricles; D008322:Mammals; D009206:Myocardium / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012978:Sodium Oxybate / Q000494:pharmacology
D000759:Adjuvants, Anesthesia; D018755:GABA Agonists; D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D018080:Receptors, GABA-B; C079148:(3-aminopropyl)(n-butyl)phosphinic acid; D012978:Sodium Oxybate; D001418:Baclofen