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

Authors: Ping Liu1,2, Yu-ling Yin1,2, Ting Wang1,2,3, Li Hou1, Xiao-xi Wang1, Man Wang1, Guan-guan Zhao1, Yi Shi1, H. Eric Xu1,2,3,4, Yi Jiang1,2
1 VARI-SIMM Center, Center for Structure and Function of Drug Targets, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
4 Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503, USA
Correspondence to: H. Eric Xu:, Yi Jiang:,
DOI: 10.1038/s41401-018-0204-6
Received: 8 September 2018
Accepted: 8 November 2018
Advance online: 4 March 2019


5-HT4R, 5-HT6R, and 5-HT7A,/SUB.R 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.
Keywords: 5-HT4R; 5-HT6R; 5-HT7AR; 5-HT; ERK1/2; Gs; β-arrestin; Fyn; Src

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