DIFFERENT ROLE OF cAMP DEPENDENT PROTEIN KINASE AND CaMKII IN H3 RECEPTOR REGULATION OF HISTAMINE SYNTHESIS AND RELEASE

Abstract Histamine H 3 autoreceptors induce a negative feedback on histamine synthesis and release. While it is known that cAMP/cAMP dependent protein kinase (PKA) and Ca 2+ /CaMKII transduction pathways mediate H 3 effects on histamine synthesis, the pathways regulating neuronal histamine release are poorly known. Given the potential use of H 3 ligands in cognitive diseases, we have developed a technique for the determination of H 3 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 (PKI 14-22 ). In contrast, forskolin stimulated histamine release, although independently of PKA. Stimulation of histamine H 3 receptors with the agonist imetit markedly reduced the depolarization increase of histamine release, apparently through P/Q calcium channel inhibition. The H 3 antagonist/inverse agonist thioperamide modestly stimulated histamine release. Thioperamide effect on release was not modified by the PKA inhibitor PKI 14-22 , but it was blocked by the CaMKII inhibitor KN-62. These results indicate that H 3 autoreceptors regulate neuronal histamine release (1) independently of the cAMP/PKA cascade, and (2) through modulation of calcium entry and CaMKII activation during depolarization.