RT Journal Article
SR Electronic
T1 Cardioprotective Effect of Histamine H<sub>3</sub>-Receptor Activation: Pivotal Role of Gβγ-Dependent Inhibition of Voltage-Operated Ca<sup>2+</sup> Channels
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 871
OP 878
DO 10.1124/jpet.108.137919
VO 326
IS 3
A1 Christopher Morrey
A1 Rima Estephan
A1 Geoffrey W. Abbott
A1 Roberto Levi
YR 2008
UL http://jpet.aspetjournals.org/content/326/3/871.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics