Ligand-induced activation of ERK1/2 signaling by constitutively active Gs-coupled 5-HT receptors.

Ping Liu, Yu-Ling Yin, Ting Wang, Li Hou, Xiao-Xi Wang, Man Wang, Guan-Guan Zhao, Yi Shi, H Eric Xu, Yi Jiang

Acta pharmacologica Sinica 2019 Sep

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5-HT4R, 5-HT6R, and 5-HT7AR are three constitutively active Gs-coupled 5-HT receptors that have key roles in brain development, learning, memory, cognition, and other physiological processes in the central nervous system. In addition to Gs signaling cascade mediated by these three 5-HT receptors, the ERK1/2 signaling which is dependent on cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) activation downstream of Gs signaling has also been widely studied. In this study, we investigated these two signaling pathways originating from the three Gs-coupled 5-HT receptors in AD293 cells. We found that the phosphorylation and activation of ERK1/2 are ligand-induced, in contrast to the constitutively active Gs signaling. This indicates that Gs signaling alone is not sufficient for ERK1/2 activation in these three 5-HT receptors. In addition to Gs, we found that β-arrestin and Fyn are essential for the activation of ERK1/2. Together, these results put forth a novel mechanism for ERK1/2 activation involving the cooperative action of Gs, β-arrestin, and Fyn.

Citation

Ping Liu, Yu-Ling Yin, Ting Wang, Li Hou, Xiao-Xi Wang, Man Wang, Guan-Guan Zhao, Yi Shi, H Eric Xu, Yi Jiang. Ligand-induced activation of ERK1/2 signaling by constitutively active Gs-coupled 5-HT receptors. Acta pharmacologica Sinica. 2019 Sep;40(9):1157-1167