Histamine H3-receptor signaling in cardiac sympathetic nerves:: Identification of a novel MAPK-PLA2-COX-PGE2-EP3R pathway

We hypothesized that the histamine H-3-receptor (H3R)-mediated attenuation of norepinephrine (NE) exocytosis from cardiac sympathetic nerves results not only from a G alpha(i)-mediated inhibition of the adenylyl cyclase-cAMP-PKA pathway, but also from a G beta gamma(i)-mediated activation of the MAPK-PLA(2) cascade, culminating in the formation of an arachidonate metabolite with anti-exocytotic characteristics (e.g., PGE(2)). We report that in Langendorff-perfused guinea-pig hearts and isolated sympathetic nerve endings (cardiac synaptosomes), H3R-mediated attenuation of K+-induced NE exocytosis was prevented by MAPK and PLA(2) inhibitors, and by cyclooxygenase and EP3-receptor (EP3R) antagonists. Moreover, H3R activation resulted in MAPK phosphorylation in H3R-transfected SH-SY5Y neuroblastoma cells, and in PLA(2) activation and PGE(2) production in cardiac synaptosomes; H3R-induced MAPK phosphorylation was prevented by an anti-beta gamma peptide. Synergism between H3R and EP3R agonists (i.e., imetit and sulprostone, respectively) suggested that PGE(2) may be a downstream effector of the anti-exocytotic effect of H3R activation. Furthermore, the anti-exocytotic effect of imetit and sulprostone was potentiated by the N-type Ca2+-channel antagonist omega-conotoxin GVIA, and prevented by an anti-G beta gamma peptide. Our findings imply that an EP3R G beta gamma(i)-induced decrease in Ca2+ influx through N-type Ca2+-channels is involved in the PGE(2)/EP3R-mediated attenuation of NE exocytosis elicited by H3R activation. Conceivably, activation of the G beta gamma(i) subunit of H3R and EP3R may also inhibit Ca2+ entry directly, independent of MAPK intervention. As heart failure, myocardial ischemia and arrhythmic dysfunction are associated with excessive local NE release, attenuation of NE release by H3R activation is cardioprotective. Accordingly, this novel H3R signaling pathway may ultimately bear therapeutic significance in hyper-adrenergic states. (c) 2007 Elsevier Inc. All rights reserved.