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H₃ Autoreceptors Modulate Histamine Synthesis through Calcium/Calmodulin- and cAMP-Dependent Protein Kinase Pathways

Universitat Autonoma de Barcelona, Neuroscience Institute, Department of Biochemistry and Molecular Biology, Bellaterra, Spain (A.T., D.M.-D., J.G.-R., I.B., J.O.); and Universidad de Málaga, Department of Molecular Biology and Biochemistry, Málaga, Spain (D.R.-A., C.R.-C., F.S.-J.)

H₃ autoreceptors provide feedback control of neurotransmitter synthesis in histaminergic neurons, but the transduction pathways involved are poorly understood. In rat brain cortical slices, histamine synthesis can be stimulated by depolarization and inhibited by H₃ agonists. We show that histamine synthesis stimulation by depolarization with 30 mM K⁺ requires extracellular calcium entry, mostly through N-type channels, and subsequent activation of calcium/calmodulin-dependent protein kinase type II. In vitro, this kinase phosphorylated and activated histidine decarboxylase, the histamine-synthesizing enzyme. Inhibition of depolarization-stimulated histamine synthesis by the histamine H₃ receptor agonist imetit was impaired by preincubation with pertussis toxin and by the presence of a myristoylated peptide (myristoyl-N-QEHAQEPERQYMHIGTMVE-FAYALVGK) blocking the actions of G-protein subunits. The stimulation of another G_i/o-coupled receptor, adenosine A₁, also decreased depolarization-stimulated histamine synthesis. In contrast, protein kinase A activation, which is also repressed by H₃ receptors, elicited a depolarization- and calcium/calmodulin-independent stimulation of histamine synthesis. Protein kinase A was able also to phosphorylate and activate histidine decarboxylase in vitro. These results show how depolarization activates histamine synthesis in nerve endings and demonstrate that both pathways modulating neurotransmitter synthesis are controlled by H₃ autoreceptors.

Address correspondence to: Dr. Jordi Ortiz, Universitat Autonoma de Barcelona, Dept. Biochemistry and Molecular Biology, School of Medicine, Neuroscience Institute, Room M2-120, E-08193 Bellaterra, Spain. E-mail: jordi.ortiz{at}uab.es

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