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  • de Valdivia, Ernesto Gonzalez, et al. (författare)
  • Roles of PDZ-dependent Interactions and N-glycosylation in G Protein-coupled Estrogen Receptor 1 (GPER1)/GPR30-mediated Stimulation of ERK1/2 Activity
  • 2018
  • Ingår i: FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 32:1 Suppl, s. 6-685
  • Konferensbidrag (refereegranskat)abstract
    • G protein-coupled receptor 30 (GPR30) is a G protein-coupled receptor (GPCR) that is attracting considerable attention in breast cancer and cardiometabolic regulation. Following reports that GPR30 is required for some rapid estrogen responses, e.g. increased cAMP production and ERK1/2 activity, in estrogen receptor (ER)-negative cells, GPR30 was renamed G protein-coupled estrogen receptor 1 (GPER1). However, many questions remain about the identity of the cognate receptor ligand, receptor-effector coupling, and receptor membrane trafficking. To address the mechanism by which human GPR30 activates ERK1/2, we used HEK293 cells with and without ectopic expression of GPR30. Specifically, we investigated the role of the type I PSD-95/Discs-large/ZO-1 homology (PDZ) motif at the receptor C terminus (-SSAV) and three consensus sites for N glycosylation (N-X-S/T) in the receptor N-terminal domain (N25, N32, N44). We found previously that the C-terminal PDZ motif enables the receptor to interact with SAP97 and protein kinase A (PKA)-anchoring protein (AKAP) 5, and this interaction is necessary for retaining the receptor in the plasma membrane and mediating a constitutive decrease in cAMP production that is not inhibited by pertussis toxin, thus independent of Gi/o. Here, we found that the receptor also constitutively increases ERK1/2 activity. Interestingly, this increase was inhibited by PTX as well as by wortmannin, but not by AG1478, indicating it is mediated by Gi/o and phosphoinositide 3-kinase (PI3K) but not epidermal growth factor receptor (EGFR) transactivation. Deleting the receptor PDZ motif or knocking down AKAP5 also inhibited the increase, showing that the PDZ interaction is also necessary for this response. Interestingly, the proposed GPR30 agonist G-1 increased ERK1/2 activity in a GPR30-dependent manner, but this increase was only observed at very low levels of receptor expression below that required for the constitutive increase. Furthermore, deleting the PDZ motif, which completely inhibited the constitutive increase in ERK1/2 activity, did not inhibit the G-1-stimulated increase. Mutating the potential N-glycosylation residues N25 or N32 to I in the GPR30 N-terminal domain did not prevent receptor plasma membrane expression or ERK1/2 activation. On the other hand, mutating N44 to I completely prevented both plasma membrane expression and ERK1/2 activation, and caused receptor degradation. Thus, the PDZ-dependent receptor interaction with SAP97 and AKAP5, and therefore plasma membrane retention, is necessary for constitutive GPR30-mediated stimulation of ERK1/2 activation, whereas G-1-stimulated ERK1/2 activation may remain following constitutive internalization. On the other hand, N-glycosylation of N44 appears to be necessary for maturation of the receptor to the plasma membrane. Support or Funding Information Swedish Research Council and Swedish Cancer Foundation This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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