Cardioprotective Effect of Histamine H3-Receptor Activation: Pivotal Role of Gβγ-Dependent Inhibition of Voltage-Operated Ca2+Channels
- 3 June 2008
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Journal of Pharmacology and Experimental Therapeutics
- Vol. 326 (3), 871-878
- https://doi.org/10.1124/jpet.108.137919
Abstract
We previously showed that activation of Gi/o-coupled histamine H3-receptors (H3R) is cardioprotective because it attenuates excessive norepinephrine release from cardiac sympathetic nerves. This action is characterized by a marked decrease in intraneuronal Ca2+ ([Ca2+]i), as Gαi impairs the adenylyl cyclase-cAMP-protein kinase A (PKA) pathway, and this decreases Ca2+ influx via voltage-operated Ca2+ channels (VOCC). Yet, the Gi/o-derived βγ dimer could directly inhibit VOCC, and the subsequent reduction in Ca2+ influx would be responsible for the H3R-mediated attenuation of transmitter exocytosis. In this study, we tested this hypothesis in nerve-growth factor-differentiated rat pheochromocytoma cells (PC12) stably transfected with H3R (PC12-H3) and with the Gβγ scavenger β-adrenergic receptor kinase 1 (β-ARK1)-(495-689)-polypeptide (PC12-H3/β-ARK1). Thus, we evaluated the effects of H3R activation directly on the following: 1) Ca2+ current (ICa) using the whole-cell patch-clamp technique; and 2) K+-induced exocytosis of endogenous dopamine. H3R activation attenuated both peak ICa and dopamine exocytosis in PC12-H3 but not in PC12-H3/β-ARK1 cells. Moreover, a membrane permeable phosducin-like Gβγ scavenger also prevented the antiexocytotic effect of H3R activation. In contrast, the H3R-induced attenuation of cAMP accumulation and dopamine exocytosis in response to forskolin were the same in both PC12-H3 and PC12-H3/β-ARK1 cells. Our findings reveal that although Gαi participates in the H3-mediated antiexocytotic effect when the adenylyl cyclase-cAMP-PKA pathway is stimulated, a direct Gβγ-induced inhibition of VOCC, resulting in an attenuation of ICa, plays a pivotal role in the H3R-mediated decrease in [Ca2+]i and associated cardioprotective antiexocytotic effects. The discovery of this H3R-signaling step may offer new therapeutic approaches to cardiovascular diseases characterized by hyperadrenergic activity.Keywords
This publication has 34 references indexed in Scilit:
- Analysis of Regulated Secretion Using PC12 CellsCurrent Protocols in Cell Biology, 2007
- Histamine H3-receptor signaling in cardiac sympathetic nerves: Identification of a novel MAPK-PLA2-COX-PGE2-EP3R pathwayBiochemical Pharmacology, 2007
- Dynamic Beat-to-Beat Modeling of the QT-RR Interval Relationship: Analysis of QT Prolongation during Alterations of Autonomic State versus Human Ethera-go-go-Related Gene InhibitionJournal of Pharmacology and Experimental Therapeutics, 2004
- Histamine H3-Receptor-Induced Attenuation of Norepinephrine Exocytosis: A Decreased Protein Kinase A Activity Mediates a Reduction in Intracellular CalciumJournal of Pharmacology and Experimental Therapeutics, 2004
- Modulation of L-type Ca2+ Channels by Gβγ and Calmodulin via Interactions with N and C Termini of α1CJournal of Biological Chemistry, 2000
- Facilitation of rabbit α1B calcium channels: involvement of endogenous Gβγ subunitsThe Journal of Physiology, 1998
- Cardiac L‐type Ca2+ channel triggers transmitter release in PC 12 cellsFEBS Letters, 1994
- Enhancement of N- and L-type calcium channel currents by protein kinase C in frog sympathetic neuronsNeuron, 1993
- Type-Specific Regulation of Adenylyl Cyclase by G Protein βγ SubunitsScience, 1991
- β-Adrenergic modulation of calcium channels in frog ventricular heart cellsNature, 1984