Enhanced activation of Akt and extracellular‐regulated kinase pathways by simultaneous occupancy of G q ‐coupled 5‐HT 2A receptors and G s ‐coupled 5‐HT 7A receptors in PC12 cells

The most commonly prescribed antidepressants, the serotonin (5‐HT) selective reuptake inhibitors, increase 5‐HT without targeting specific receptors. Yet, little is known about the interaction of multiple receptor subtypes expressed by individual neurons. Specifically, the effect of increases in cAMP induced by G s ‐coupled 5‐HT receptor subtypes on the signaling pathways modulated by other receptor subtypes has not been studied. We have, therefore, examined the activation of the extracellular‐regulated kinase (ERK) and Akt pathways by G s ‐coupled 5‐HT 7A receptors and G q ‐coupled 5‐HT 2A receptors, which are co‐expressed in discrete brain regions. Agonists for both receptors were found to activate ERK and Akt in transfected PC12 cells. 5‐HT 2A receptor‐mediated activation of the two pathways was found to be Ca 2+ ‐dependent. In contrast, 5‐HT 7A receptor‐mediated activation of Akt required increases in both [cAMP] and intracellular [Ca 2+ ], while activation of ERK was inhibited by Ca 2+ . The activation of ERK and Akt stimulated by simultaneous treatment of cells with 5‐HT 2A and 5‐HT 7A receptor agonists was found to be at least additive. Cell‐permeable cAMP analogs mimicked 5‐HT 7A receptor agonists in enhancing 5‐HT 2A receptor‐mediated activation of ERK and Akt. A role was identified for the cAMP–guanine exchange factor, Epac, in this augmentation of ERK, but not Akt, activation. Our finding of enhanced activation of neuroprotective Akt and ERK pathways by simultaneous occupancy of 5‐HT 2A and 5‐HT 7A receptors may also be relevant to the interaction of other neuronally expressed G q ‐ and G s ‐coupled receptors.