Enhanced activation of Akt and extracellular‐regulated kinase pathways by simultaneous occupancy of Gq‐coupled 5‐HT2Areceptors and Gs‐coupled 5‐HT7Areceptors in PC12 cells

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Abstract
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 Gs‐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 Gs‐coupled 5‐HT7Areceptors and Gq‐coupled 5‐HT2Areceptors, which are co‐expressed in discrete brain regions. Agonists for both receptors were found to activate ERK and Akt in transfected PC12 cells. 5‐HT2Areceptor‐mediated activation of the two pathways was found to be Ca2+‐dependent. In contrast, 5‐HT7Areceptor‐mediated activation of Akt required increases in both [cAMP] and intracellular [Ca2+], while activation of ERK was inhibited by Ca2+. The activation of ERK and Akt stimulated by simultaneous treatment of cells with 5‐HT2Aand 5‐HT7Areceptor agonists was found to be at least additive. Cell‐permeable cAMP analogs mimicked 5‐HT7Areceptor agonists in enhancing 5‐HT2Areceptor‐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‐HT2Aand 5‐HT7Areceptors may also be relevant to the interaction of other neuronally expressed Gq‐ and Gs‐coupled receptors.