5-Hydroxytryptamine(2C) receptor activation inhibits 5- hydroxytryptamine(1B)-like receptor function via arachidonic acid metabolism

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Abstract

We previously reported that in Chinese hamster ovary (CHO) cells, 5- hydroxytryptamine (5-HT)(1B)-like (CHO/5-HT(1B)) receptor-mediated inhibition of forskolin-stimulated cAMP accumulation is inhibited by activation of transfected human 5-HT(2C) receptors but not 5-HT(2A) receptors. In the current study, we investigated the mechanism involved in the regulation of receptor-mediated inhibition of adenylyl cyclase as a means to further elucidate differences between the signal transduction cascades of the 5- HT(2A) and 5-HT(2C) receptor subtypes. Activation of 5-HT(2C) receptors with 5-HT or (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane increased release of arachidonic acid via a phospholipase A2 (PLA2)-dependent mechanism. Incubation with (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1 μM) abolished 5-carboxamidotryptamine (5 nM)-mediated inhibition of forskolin- stimulated cAMP accumulation, which was blocked by the PLA2 inhibitor mepacrine (100 μM) and the cyclooxygenase inhibitor indomethacin (2 μM). Furthermore, purinergic receptor-mediated PLA2 activation as well as direct activation of PLA2 with melittin reduced CHO/5-HT(1B) responsiveness. These data indicate that activation of the PLA2/arachidonic acid signaling cascade mediates 5-HT(2C) receptor regulation of the CHO/5-HT(1B) receptor pathway. Consistent with our previous report and in contrast to activation of 5- HT(2C) or purinergic receptors, activation of 5-HT(2A) receptors had no effect on CHO/5-HT(1B) receptor function, although 5-HT(2A) receptor-mediated activation of PLA2 was measured. Interestingly, purinergic receptor-mediated inhibition of CHO/5-HT(1B) receptor function was blocked when 5-HT(2A) receptors were activated simultaneously. These data suggest that the lack of 5-HT(2A)-mediated regulation of CHO/5-HT(1B) receptors may be due to activation of a third pathway (in addition to PLC and PLA2 pathways), which results in the inhibition of the production or the actions of a cyclooxygenase-dependent arachidonic acid metabolite.

Original languageEnglish (US)
Pages (from-to)1017-1023
Number of pages7
JournalMolecular pharmacology
Volume50
Issue number4
StatePublished - Oct 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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