A complex signaling cascade links the serotonin_2A receptor to phospholipase A₂ activation: the involvement of MAP kinases

Abstract

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 Ga 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 Ga i/o , as well as pertussis toxin-insensitive G proteins, namely Ga 12/13 , in 5-HT-induced AA release. Furthermore, inactivation of both Gbc 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 Ga i/o -associated Gbc-mediated ERK1,2 activation and Ga 12/13 -coupled, Rho-mediated p38 activation.

Role of Gq protein in behavioral effects of the hallucinogenic drug 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane

“…Compensatory changes, for instance, in G 11 or in other components of the signaling complex, such as RGS proteins, may differ within the relevant brain sites, leading to the differential sensitivity of the two behaviors. Alternatively, some other signaling pathway, e.g., G 13 activation of PLD (McGrew et al, 2002;Kurrasch-Orbaugh et al, 2003) or G i/o activation of the erg signaling pathway (Gonzales Maeso et al, 2007), may contribute to the head-twitch behavior. How this differential behavioral sensitivity in G q null mice relates to human hallucinogenic drug experience is not known.…”

The role of phospholipases A2 in schizophrenia

“…5,6,11,103 An increasing body of evidence suggests that AA is altered in schizophrenia in a causative manner:…”

“…8,9 The polyunsaturated fatty acid (PUFA) AA itself is a potent signalling molecule, and also the precursor for a range of messengers (eicosanoids) necessary for normal neuronal function. 10,11 To limit aberrant signalling AA is usually bound to cell membranes phospholipids. In addition to creating a reservoir for later release of AA in response to appropriate signals, the ratio of saturated to unsaturated fatty acids (such as AA) also defines membrane fluidity, which alters the activity of membrane bound proteins including neurotransmitter receptors.…”

“…5,11,17,28 The colocalisation of monoaminergic receptors with PLA2G4A, PLA2G2A and eicosanoid-synthesising enzymes further emphasise their importance for monoaminergic neurotransmission. 15,[29][30][31] The proper functioning and availability of these PLA2s are therefore crucial for G-proteincoupled neurotransmission.…”

An immunocapture/scintillation proximity analysis of Gαq/11 activation by native serotonin (5‐HT)2A receptors in rat cortex: Blockade by clozapine and mirtazapine

“…Moreover, they were reported to directly couple with monomeric Gproteins such as RhoA or ARF1, thereby activating phospholipase D (PLD) and producing phosphatidic acid (Kurrasch-Orbaugh et al, 2003a;Mitchell et al, 1998;Robertson et al, 2003). Furthermore, 5-HT 2A receptors can also mediate ERK1/2 and p38 activation through the recruitment of Gi/o and G12/13 proteins, respectively (Kurrasch-Orbaugh et al, 2003b;Watts, 1998).…”