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A complex signaling cascade links the serotonin 2A receptor to phospholipase A 2 activation: the involvement of MAP kinases
Author(s) -
KurraschOrbaugh Deborah M.,
Parrish Jason C.,
Watts Val J.,
Nichols David E.
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01921.x
Subject(s) - pertussis toxin , receptor , signal transduction , microbiology and biotechnology , agonist , g protein , phospholipase c , g protein coupled receptor , phosphorylation , kinase , p38 mitogen activated protein kinases , gi alpha subunit , chemistry , gq alpha subunit , biology , biophysics , mapk/erk pathway , biochemistry
Previous studies in our laboratory have shown that in NIH3T3–5HT 2A cells, 5‐HT‐induced AA release is PLA 2 ‐coupled and independent of 5‐HT 2A receptor‐mediated PLC activation. Although 5‐HT 2A receptor‐mediated PLC activation is known to be Gα q ‐coupled, much less is understood about 5‐HT 2A receptor‐mediated PLA 2 activation. Therefore, the studies presented here were aimed at elucidating the signal transduction pathway linking stimulation of the 5‐HT 2A receptor to PLA 2 activation. By employing various selective inhibitors, toxins, and antagonistic peptide constructs, we propose that the 5‐HT 2A receptor can couple to PLA 2 activation through two parallel signaling cascades. Initial experiments were designed to examine the role of pertussis toxin‐sensitive G proteins, namely Gα i/o , as well as pertussis toxin‐insensitive G proteins, namely Gα 12/13 , 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‐HT 2A 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‐HT 2A receptor expressed in NIH3T3 cells can couple to PLA 2 activation though a complex signaling mechanism involving both Gα i/o ‐associated Gβγ‐mediated ERK1,2 activation and Gα 12/13 ‐coupled, Rho‐mediated p38 activation.