Constitutive activity of H3 autoreceptors modulates histamine synthesis in rat brain through the cAMP/PKA pathway

David Moreno-Delgado, Anna Torrent, Jordi Gómez-Ramírez, Iwan de Esch, Isaac Blanco, Jordi Ortiz*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

32 Citations (Scopus)


We previously described that agonist-activated histamine H3 autoreceptors inhibit the stimulation of histamine synthesis mediated by calcium/calmodulin- and cAMP-dependent protein kinases (CaMKII and PKA respectively) in histaminergic nerve endings. In the absence of an agonist H3 receptors show partial constitutive activity, so we hypothesized that suppression of constitutive activity by an inverse agonist could stimulate these transduction pathways. We show here that the H3 inverse agonist thioperamide increases histamine synthesis in rat brain cortical slices independently from the amounts of extracellular histamine. Thioperamide effects were mimicked by the inverse agonists clobenpropit and A-331440, but not by the neutral antagonist VUF-5681. In contrast, coincubation with VUF-5681 suppressed thioperamide effects. The effects of thioperamide were completely blocked by the PKA inhibitor peptide myristoyl-PKI14-22, a peptide that did not block depolarization stimulation of histamine synthesis. In addition, thioperamide effects required depolarization and were impaired by blockade of N-type calcium channels (mediating depolarization), but not by CaMKII inhibition. These results indicate that constitutive activity of H3 receptors in rat brain cortex inhibits the adenylate cyclase/PKA pathway, and perhaps also the opening of N-type voltage sensitive calcium channels, but apparently not CaMKII.

Original languageAmerican English
Pages (from-to)517-523
Number of pages7
Issue number3
Publication statusPublished - Sept 2006


  • Histamine H3 receptors
  • Inverse agonism
  • PKA
  • Protean agonism
  • Signal transduction


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