G protein-coupled receptors (GPCRs): families, modules and functions

SCOPING BIOLOGY_DOMAINFLAGSHIP

Species: human

Genes: ADRB2 ADGRV1 FZD7 GPR101 GPR161 CASR GNAS OPRM1

G protein-coupled receptors (GPCRs): families, modules and functions

Bottom line: GPCRs are the largest receptor superfamily in the human genome
and the targets of a large share of approved drugs, yet only a handful have a
review here (human ADRB2, ADGRV1, FZD7, GPR101, GPR161, CASR and OPRM1, plus the transducer GNAS). This
project curates the superfamily on three levels: families (whether
PANTHER/PAINT and InterPro propagation of GPCR terms is safe), modules
(the transducer pathways downstream of the receptors), and gene functions
(per-gene reviews, starting with receptors that are drug targets). It is
paired with the dismech project
GPCR drug mechanisms and disease modules,
which uses the same receptors as the molecular anchors for drug-mechanism and
disease modules.

Why GPCRs

Workstream 1 — Families

Review PANTHER families for the coherence of GPCR terms, following the
Protein Families and IBA review conventions.
Candidate families (ids and names read from interpro/panther/panther.obo;
membership still to be checked against the PANTHER member index before any
module uses them):

PANTHER id PANTHER name Question
PTHR24248 ADRENERGIC RECEPTOR-RELATED G-PROTEIN COUPLED RECEPTOR Which aminergic subfamilies does it contain, and at what node does Gs vs Gi/o vs Gq coupling diverge?
PTHR24247 5-HYDROXYTRYPTAMINE RECEPTOR Same coupling question across 5-HT1/2/4/6/7.
PTHR24249 HISTAMINE RECEPTOR-RELATED G-PROTEIN COUPLED RECEPTOR H1 (Gq) vs H2 (Gs) vs H3/H4 (Gi/o).
PTHR24246 OLFACTORY RECEPTOR AND ADENOSINE RECEPTOR A mixed family name; check what the adenosine receptors share with ORs.
PTHR26452, PTHR26453, PTHR26454 OLFACTORY RECEPTOR Deferred (see Decisions).
PTHR11394 TASTE RECEPTOR TYPE 2 Bitter-taste receptors; extra-oral roles.
PTHR24060 METABOTROPIC GLUTAMATE RECEPTOR Class C; glutamate vs GABA-B vs CaSR divergence.
PTHR24061 CALCIUM-SENSING RECEPTOR-RELATED CASR, GPRC6A, taste type 1.
PTHR12011 ADHESION G-PROTEIN COUPLED RECEPTOR Many members have no demonstrated G protein coupling; tethered-agonist mechanism.
PTHR11309 FRIZZLED Wnt receptors: is GO:0004930 justified, or should coupling be left to SMO-like evidence?
PTHR11334 MAS-RELATED G-PROTEIN COUPLED RECEPTOR Primate-expanded MRGPRs; itch/mast-cell ligands.
PTHR11792 ARRESTIN Visual vs beta-arrestins; scaffolding functions.
PTHR24355 G PROTEIN-COUPLED RECEPTOR KINASE/RIBOSOMAL PROTEIN S6 KINASE A family that mixes GRKs with S6 kinases; kinase substrate terms must not cross the split.

Several PANTHER families are named only "G-PROTEIN COUPLED RECEPTOR"
(e.g. PTHR22750, PTHR24230, PTHR24232); their contents are to be identified
from the member index, not guessed from the name.

Deliverable per family: a family review (coherence call, term-scope calls for
GO:0004930, the coupling BP terms, and the ligand-specific MF terms), and
IBA findings feeding IBA_REVIEW.

Workstream 2 — Modules

Two GPCR modules exist as drafts: gpcr_camp_pka_signaling (Gs) and
gpcr_plc_calcium_pkc_signaling (Gq). Related existing modules:
chemokine_signaling, wnt_signaling, hedgehog_signaling.

Planned work, using the module-curation skill:

  1. Promote the two drafts: ground GNAS, ADCY5, PRKACA, CREB1 and the Gq
    parts in PAINT nodes where the evidence is clear; otherwise leave PTN
    claims out.
  2. Gi/o inhibitory module: Gi/o alpha inhibition of adenylyl cyclase plus
    G beta-gamma activation of GIRK channels and inhibition of voltage-gated
    calcium channels (the opioid, D2, alpha2, M2 and GABA-B arm).
  3. G12/13-RhoA module: Galpha12/13, RhoGEFs (ARHGEF1/11/12), RhoA-ROCK.
  4. Receptor desensitization and arrestin module: GRK phosphorylation,
    arrestin recruitment, clathrin-dependent internalization, recycling vs
    degradation. This is where GO:1904022 positive regulation of G
    protein-coupled receptor internalization and the arrestin-scaffold terms
    belong.
  5. RGS GAP module: RGS-accelerated GTP hydrolysis terminating signaling
    (RGS4 and the R7/R4 subfamilies).
  6. Rod phototransduction as a well-characterized exemplar (rhodopsin,
    transducin, PDE6, GRK1, visual arrestin), if no existing module already
    covers it.

Each module should list the receptor gene reviews it depends on; a module
part with no reviewed gene is a curation gap recorded in the module notes.

Workstream 3 — Gene functions

Per-gene reviews with the review skill. Order by how much each review
unblocks: a receptor that anchors a dismech drug-mechanism module, a module
part, or a family review comes first.

Tranche 1 — drug-target receptors (each anchors a dismech module):
ADRB1, ADRB2 (refresh), ADRA1A, ADRA2A, DRD2, HTR2A, HTR1B, HTR1D, OPRM1,
HRH1, HRH2, AGTR1, GLP1R, GIPR, CASR (refresh), CHRM3, S1PR1, P2RY12, CNR1, MC4R,
CALCRL, TSHR.

Tranche 2 — transducers and regulators (module parts): GNAS (refresh), GNAI1,
GNAI2, GNAO1, GNAQ, GNA11, GNA12, GNA13, GNB1, GNG2, ARRB1, ARRB2, GRK2,
GRK3, GRK5, GRK6, RGS2, RGS4, ADCY5, PLCB1.

Tranche 3 — disease-gene receptors without a drug (feed dismech disease
modules): RHO, OPN1LW, MC2R, PTH1R, AVPR2, GNRHR, KISS1R, LHCGR, FSHR,
GPR143, ADGRG1, ADGRV1 (refresh), FZD4.

Recurring function questions to resolve while reviewing:

First pairing: mu-opioid receptor

Chosen as the first receptor (2026-10-15) because dismech already has many
opioid-treated entries waiting for a shared mechanism module. Gene side:

The dismech side builds the mu-opioid agonism and antagonism modules on top.

Plan

Decisions

Open questions