GPER1 (G protein-coupled estrogen receptor 1; GPR30; CMKRL2) review notes

Deep research status: falcon (Edison) deep research failed with an authentication
error on 2026-10-24, and no other deep-research provider key was usable. No
-deep-research-*.md file exists for this gene. The notes below come from the cached
publications in publications/, the UniProt record (GPER1-uniprot.txt), cached
Reactome entries, GO term definitions (oaklib, sqlite:obo:go) and a web search.

Why this gene was reviewed

Flagged by rule FRR:0009 (projects/FUNCTION_REQUIREMENT_RULES.md): GPER1 carries
GO:0030284 nuclear estrogen receptor activity (IDA x2, IBA, IEA), a descendant of
GO:0003700 DNA-binding transcription factor activity, while having no DNA-binding domain.

GO definition check (oaklib, go.db):
- GO:0030284 nuclear estrogen receptor activity: "A nuclear receptor activity regulated
by estrogen binding and modulating the transcription of specific gene sets transcribed
by RNA polymerase II." Parent GO:0003707 nuclear steroid receptor activity; GO:0003700
is an ancestor (confirmed).
- GO:0038054 G protein-coupled estrogen receptor activity: "Combining with estrogen and
transmitting the signal across the membrane by activating an associated G-protein..."
is_a GO:0004930 G protein-coupled receptor activity. This is the term that matches GPER1.
- GO:0030520 estrogen receptor signaling pathway and GO:0030518 are both defined as
nuclear-receptor-mediated pathways; GO:0043401 steroid hormone receptor signaling
pathway is the receptor-type-neutral parent.
- GO:1903924 estradiol binding exists (is_a steroid binding).

Domain architecture / family

• UniProt: "Belongs to the G protein-coupled receptor 1 family" (PROSITE-ProRule PRU00521);
  Pfam PF00001 7tm_1; InterPro IPR000276/IPR017452 (rhodopsin-like GPCR), IPR047143
  GPER1-like; PANTHER PTHR24226:SF2 (G-protein coupled estrogen receptor 1), family
  PTHR24226 (GPR182 and GPER1). No nuclear-receptor zinc finger or ligand-binding domain.
• 375 aa; 7 TM helices; C-terminal PDZ-binding motif (-SSAV) PMID:38211639.

Receptor activity and ligand binding

• PMID:15539556
• PMID:15539556
• Kd ~2.7 nM in SKBR3 membranes PMID:15539556.
• PMID:15705806; PMID:15705806.
  NB: the abstract describes PIP3 (a lipid), whereas GOA annotates
  GO:0032962 positive regulation of inositol trisphosphate biosynthetic process from this paper (likely term error; recorded as a source defect, CHECK).
• Conserved in fish: PMID:19931550.
• Contrary evidence: PMID:18566127; PMID:18566127. UniProt CAUTION notes conflicting data. Web search (PMC7137379, "Does GPER really function as a G protein-coupled estrogen receptor in vivo?", Front Endocrinol 2020) summarises ongoing debate; IUPHAR named the receptor GPER in 2007. Not cached; used as context only.
• Reactome models GPER as a Gs- and Gi-coupled GPCR for estradiol [Reactome:R-HSA-9036301 "Binding of E2 to GPER induces the exchange of GDP for GTP on the G alpha (s) heterotrimer G protein, activating it"].
• UniProt also states aldosterone receptor function (by similarity) - contested.

Signalling outputs (downstream; mostly non-core)

• UniProt FUNCTION: cAMP, calcium mobilization, Src -> HB-EGF release -> EGFR transactivation -> PI3K/Akt and ERK.
• CAFs: PMID:20551055 - the basis of chromatin binding / transcription annotations. A 7TM receptor acting on chromatin is unusual and not independently established; treated as over-annotation.
• Myometrium: PMID:21427217.
• Endothelium: PMID:23285008; leukocytes themselves were not assayed.
• Coronary artery SMCs: PMID:23840305 - note opposite sign to ERK activation in other cells; context dependent.

Localization

• Plasma membrane: cAMP and beta-arrestin2 recruitment at PM PMID:21149639.
• Constitutive endocytosis, recycling endosomes, TGN, proteasomal degradation PMID:21540189; PMID:21540189. This explains low steady-state surface levels and resolves the PM-vs-ER controversy; hence the NOT|plasma membrane row from PMID:15705806 is contradicted.
• ER: PMID:18566127.
• Keratin filaments PMID:21149639.
• Nucleus in HUVEC PMID:23285008 and in CAFs (PMID:20551055).

Interactions

• RAMP3 PMID:23674134; RAMP1/2/3 screen (PMID:39083597).
• NHERF1 via PDZ PMID:27448983.
• beta1AR/MAGUK/AKAP5 complex (PMID:38211639).
• KRT7/KRT8 (PMID:21149639); EGFR (PMID:20551055).

Decisions summary

• GO:0030284 (all four rows): MODIFY -> GO:0038054 G protein-coupled estrogen receptor activity; source_defects WRONG_TERM against UniProt (IDA), GO_Central/PAINT PTN002795969 (IBA) and MGI (source of the Ensembl Compara IEA).
• GO:0004930 rows: MODIFY -> GO:0038054 (more specific, supported).
• steroid binding / steroid hormone binding: MODIFY -> GO:1903924 estradiol binding.
• GO:0030518 / GO:0030520 (nuclear-receptor pathways): MODIFY -> GO:0043401.
• GO:0045745 positive regulation of GPCR signaling: MODIFY -> GO:0007189 / GO:0007186 (GPER is the receptor itself).
• Downstream signalling/physiology terms: mostly KEEP_AS_NON_CORE; terms implying GPER responds to TNF, oxytocin or glucose, or executes apoptotic nuclear changes or action potentials: MARK_AS_OVER_ANNOTATED.
• Generic protein binding: REMOVE, except NHERF1 -> MODIFY to PDZ domain binding.