Histamine H3-Receptor-Induced Attenuation of Norepinephrine Exocytosis: A Decreased Protein Kinase A Activity Mediates a Reduction in Intracellular Calcium
- 11 August 2004
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 312 (1), 272-280
- https://doi.org/10.1124/jpet.104.072504
Abstract
We had reported that activation of presynaptic histamine H3-receptors inhibits norepinephrine exocytosis from depolarized cardiac sympathetic nerve endings, an action associated with a marked decrease in intraneuronal Ca2+ that we ascribed to a decreased Ca2+ influx. An H3-receptor-mediated inhibition of cAMP-dependent phosphorylation of Ca2+ channels could cause a sequential attenuation of Ca2+ influx, intraneuronal Ca2+ and norepinephrine exocytosis. We tested this hypothesis in sympathetic nerve endings (cardiac synaptosomes) expressing native H3-receptors and in human neuroblastoma SH-SY5Y cells transfected with H3-receptors. Norepinephrine exocytosis was elicited by K+ or by stimulation of adenylyl cyclase with forskolin. H3-receptor activation markedly attenuated the K+- and forskolin-induced norepinephrine exocytosis; pretreatment with pertussis toxin prevented this effect. Similar to forskolin, 8-bromo-cAMP elicited norepinephrine exocytosis but, unlike forskolin, it was unaffected by H3-receptor activation, demonstrating that inhibition of adenylyl cyclase is a pivotal step in the H3-receptor transductional cascade. Indeed, we found that H3-receptor activation attenuated norepinephrine exocytosis concomitantly with a decrease in intracellular cAMP and PKA activity in SH-SY5Y-H3 cells. Moreover, pharmacological PKA inhibition acted synergistically with H3-receptor activation to reduce K+-induced peak intracellular Ca2+ in SH-SY5Y-H3 cells and norepinephrine exocytosis in cardiac synaptosomes. Furthermore, H3-receptor activation synergized with N- and L-type Ca2+ channel blockers to reduce norepinephrine exocytosis in cardiac synaptosomes. Our findings suggest that the H3-receptor-mediated inhibition of norepinephrine exocytosis from cardiac sympathetic nerves results sequentially from H3-receptor-Gi/Go coupling, inhibition of adenylyl cyclase activity, and decreased cAMP formation, leading to diminished PKA activity, and thus, decreased Ca2+ influx through voltage-operated Ca2+ channels.Keywords
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