H3 autoreceptors modulate histamine synthesis through calcium/calmodulin- and cAMP-dependent protein kinase pathways.
H(3) 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 H(3) 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 H(3) 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 betagamma subunits. The stimulation of another G(i/o)-coupled receptor, adenosine A(1), also decreased depolarization-stimulated histamine synthesis. In contrast, protein kinase A activation, which is also repressed by H(3) 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 H(3) autoreceptors.
Torrent
Anna
A
Universitat Autonoma de Barcelona, Dept. Biochemistry and Molecular Biology, School of Medicine, Neuroscience Institute, Room M2-120, E-08193 Bellaterra, Spain.
Moreno-Delgado
David
D
Gómez-Ramírez
Jordi
J
Rodríguez-Agudo
Daniel
D
Rodríguez-Caso
Carlos
C
Sánchez-Jiménez
Francisca
F
Blanco
Isaac
I
Ortiz
Jordí
J
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006632:Histamine / Q000096:biosynthesis*; D017442:Histamine Agonists / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
D002121:Calcium Channel Blockers; D017442:Histamine Agonists; D007093:Imidazoles; D010446:Peptide Fragments; D018100:Receptors, Histamine H3; D011994:Recombinant Proteins; C077430:imetit; D006632:Histamine; D037342:Pertussis Toxin; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D006640:Histidine Decarboxylase; D013890:Thiourea