Different role of cAMP dependent protein kinase and CaMKII in H3 receptor regulation of histamine synthesis and release

D. Moreno-Delgado, J. Gómez-Ramírez, A. Torrent-Moreno, M. González-Sepúlveda, I. Blanco, J. Ortiz

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Histamine H3 autoreceptors induce a negative feedback on histamine synthesis and release. While it is known that cAMP/cAMP dependent protein kinase (PKA) and Ca2+/CaMKII transduction pathways mediate H3 effects on histamine synthesis, the pathways regulating neuronal histamine release are poorly known. Given the potential use of H3 ligands in cognitive diseases, we have developed a technique for the determination of H3 effects on histamine synthesis and release in brain cortical miniprisms. Potassium-induced depolarization effects were impaired by blockade of calcium entry through N and P/Q channels, as well as of CaMKII, but release was not affected by activators or inhibitors of the cAMP/PKA pathway (1-methyl-3-isobutylxanthine (IBMX), N6,2′-O-dibutyryladenosine 3′,5′-cyclic monophosphate sodium salt (db-cAMP) or myristoyl PKA inhibitor peptide 14-22 (PKI14-22). In contrast, forskolin stimulated histamine release, although independently of PKA. Stimulation of histamine H3 receptors with the agonist imetit markedly reduced the depolarization increase of histamine release, apparently through P/Q calcium channel inhibition. The H3 antagonist/inverse agonist thioperamide modestly stimulated histamine release. Thioperamide effect on release was not modified by the PKA inhibitor PKI14-22, but it was blocked by the CaMKII inhibitor KN-62. These results indicate that H3 autoreceptors regulate neuronal histamine release (1) independently of the cAMP/PKA cascade, and (2) through modulation of calcium entry and CaMKII activation during depolarization. © 2009 IBRO.
Idioma originalInglés
Páginas (desde-hasta)1244-1251
EstadoPublicada - 15 dic 2009


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