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A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinases

Previous studies in our laboratory have shown that in NIH3T3–5HT2A cells, 5‐HT‐induced AA release is PLA2‐coupled and independent of 5‐HT2A receptor‐mediated PLC activation. Although 5‐HT2A receptor‐mediated PLC activation is known to be Gαq‐coupled, much less is understood about 5‐HT2A receptor‐mediated PLA2 activation. Therefore, the studies presented here were aimed at elucidating the signal transduction pathway linking stimulation of the 5‐HT2A receptor to PLA2 activation. By employing various selective inhibitors, toxins, and antagonistic peptide constructs, we propose that the 5‐HT2A receptor can couple to PLA2 activation through two parallel signaling cascades. Initial experiments were designed to examine the role of pertussis toxin‐sensitive G proteins, namely Gαi/o, as well as pertussis toxin‐insensitive G proteins, namely Gα12/13, in 5‐HT‐induced AA release. Furthermore, inactivation of both Gβγ heterodimers and Rho proteins resulted in decreased agonist‐induced AA release, without having any effect on PLC‐IP accumulation. We also demonstrated 5‐HT2A receptor‐mediated phosphorylation of ERK1,2 and p38. Moreover, pretreatment with selective ERK1,2 and p38 inhibitors resulted in decreased 5‐HT‐induced AA release. Taken together, these results suggest that the 5‐HT2A receptor expressed in NIH3T3 cells can couple to PLA2 activation though a complex signaling mechanism involving both Gαi/o‐associated Gβγ‐mediated ERK1,2 activation and Gα12/13‐coupled, Rho‐mediated p38 activation.