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Updated: Mar 3, 2026
Spatial and Temporal Analysis of Active ERK in the C. elegans Germline
Published on: November 29, 2016
G protein-coupled estrogen receptor 1 (GPER1)/GPR30 increases ERK1/2 activity through PDZ motif-dependent and
Ernesto Gonzalez de Valdivia1, Stefan Broselid1, Robin Kahn2
1From the Departments of Experimental Medical Science.
Abstract:
G protein-coupled receptor 30 (GPR30), also called G protein-coupled estrogen receptor 1 (GPER1), is thought to play important roles in breast cancer and cardiometabolic regulation, but many questions remain about ligand activation, effector coupling, and subcellular localization. We showed recently that GPR30 interacts through the C-terminal type I PDZ motif with SAP97 and protein kinase A (PKA)-anchoring protein (AKAP) 5, which anchor the receptor in the plasma membrane and mediate an apparently constitutive decrease in cAMP production independently of Gi/o Here, we show that GPR30 also constitutively increases ERK1/2 activity. Removing the receptor PDZ motif or knocking down specifically AKAP5 inhibited the increase, showing that this increase also requires the PDZ interaction. However, the increase was inhibited by pertussis toxin as well as by wortmannin but not by AG1478, indicating that Gi/o and phosphoinositide 3-kinase (PI3K) mediate the increase independently of epidermal growth factor receptor transactivation. FK506 and okadaic acid also inhibited the increase, implying that a protein phosphatase is involved. The proposed GPR30 agonist G-1 also increased ERK1/2 activity, but this increase was only observed at a level of receptor expression below that required for the constitutive increase. Furthermore, deleting the PDZ motif did not inhibit the G-1-stimulated increase. Based on these results, we propose that GPR30 increases ERK1/2 activity via two Gi/o-mediated mechanisms, a PDZ-dependent, apparently constitutive mechanism and a PDZ-independent G-1-stimulated mechanism.
Insights
G protein-coupled receptor 30 (GPR30) constitutively increases ERK1/2 activity through a PDZ-dependent mechanism. A separate G-1-stimulated pathway also activates ERK1/2 independently of the PDZ motif.
Area of Science:
- Molecular Biology
- Cell Signaling
- Endocrinology
Background:
- G protein-coupled receptor 30 (GPR30/GPER1) is implicated in breast cancer and cardiometabolic regulation.
- Its precise mechanisms of ligand activation, effector coupling, and localization remain incompletely understood.
- Previous work identified GPR30 interaction with SAP97 and AKAP5 via a PDZ motif, anchoring it to the plasma membrane and decreasing cAMP production.
Purpose of the Study:
- To investigate the role of GPR30 in regulating ERK1/2 activity.
- To elucidate the signaling pathways and protein interactions involved in GPR30-mediated ERK1/2 activation.
- To differentiate between constitutive and ligand-stimulated GPR30 signaling.
Main Methods:
- Investigated GPR30's effect on ERK1/2 activity in cells.
- Utilized receptor PDZ motif deletion and AKAP5 knockdown.
- Employed pertussis toxin, wortmannin, AG1478, FK506, and okadaic acid to probe signaling pathways.
- Administered GPR30 agonist G-1 to assess ligand-stimulated responses.
Main Results:
- GPR30 constitutively increases ERK1/2 activity in a PDZ-dependent manner requiring Gi/o and PI3K, but not EGFR transactivation.
- This constitutive activation is inhibited by protein phosphatase inhibitors.
- G-1 stimulation also increases ERK1/2 activity via a PDZ-independent, Gi/o-mediated pathway, observed at lower receptor expression levels.
Conclusions:
- GPR30 activates ERK1/2 through at least two distinct Gi/o-mediated pathways.
- One pathway is constitutive, PDZ-dependent, and involves AKAP5.
- The second pathway is ligand-stimulated (G-1), PDZ-independent, and differentially regulated.
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