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Modifying ligand-induced and constitutive signaling of the human 5-HT4receptor

  • Author(s): Chang, WC
  • Ng, JK
  • Nguyen, T
  • Pellissier, L
  • Claeysen, S
  • Hsiao, EC
  • Conklin, BR
  • et al.

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G protein-coupled receptors (GPCRs) signal through a limited number of G-protein pathways and play crucial roles in many biological processes. Studies of their in vivo functions have been hampered by the molecular and functional diversity of GPCRs and the paucity of ligands with specific signaling effects. To better compare the effects of activating different G-protein signaling pathways through ligand-induced or constitutive signaling, we developed a new series of RASSLs (receptors activated solely by synthetic ligands) that activate different G-protein signaling pathways. These RASSLs are based on the human 5-HT4breceptor, a GPCR with high constitutive Gssignaling and strong ligand-induced G-protein activation of the Gsand Gs/qpathways. The first receptor in this series, 5-HT4-D100A or Rs1 (RASSL serotonin 1), is not activated by its endogenous agonist, serotonin, but is selectively activated by the small synthetic molecules GR113808, GR125487, and RO110-0235. All agonists potently induced Gssignaling, but only a few (e.g., zacopride) also induced signaling via the Gqpathway. Zacoprideinduced Gqsignaling was enhanced by replacing the C-terminus of Rs1 with the C-terminus of the human 5-HT2Creceptor. Additional point mutations (D66A and D66N) blocked constitutive Gssignaling and lowered ligand-induced Gqsignaling. Replacing the third intracellular loop of Rs1 with that of human 5-HT1Aconferred ligand-mediated Gisignaling. This Gi-coupled RASSL, Rs1.3, exhibited no measurable signaling to the Gsor Gqpathway. These findings show that the signaling repertoire of Rs1 can be expanded and controlled by receptor engineering and drug selection. © 2007 Chang et al.

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This item is under embargo until December 31, 2999.