GNAI3 (Gi alpha-3, UniProt P08754) - curation notes

Session 2026-10-23

just deep-research-falcon human GNAI3 --fallback perplexity-lite was run twice and failed both times:
falcon (Edison) returned Exception: Failed to authenticate; the perplexity-lite fallback reported
Provider 'perplexity' not available. Available: openai, falcon, openscientist. No deep-research file
exists for this gene; the review below is based on the UniProt record, the GOA rows and the cached
primary literature in publications/.

354-aa G alpha subunit, G(i/o/t/z) subfamily of the G-alpha family; G-alpha domain 32-354 with G1/G2
motifs (UniProt P08754). Initiator Met removed; N-terminal lipid anchor (UniProt: "Lipid-anchor").
Originally cloned from differentiated HL-60 cells as "Gx alpha" PMID:3109953

UniProt function: "The alpha chain contains the guanine nucleotide binding site and alternates between
an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes
GDP release and GTP binding." (P08754 FUNCTION, by similarity to GNAI1 P08753).
RGS proteins act as GAPs on Gai3: PMID:8774883 and ["RGS10 increases potently and
selectively the GTP hydrolytic activity of several members of the G alphai family, including G alphai3,
G alphaz, and G alpha0."]
Structural RGS/Galpha work PMID:18434541; RGS2 triple mutant gains Gai-directed GAP activity PMID:19478087. Abstract-only in cache;
the curator's IDA rows (GTPase activity, GDP binding, AC-inhibiting GPCR pathway, GTP metabolic
process) were made from the full text.

Adenylyl cyclase inhibition (canonical Gi): m2 muscarinic receptors couple to AC inhibition through
Gai3 PMID:7608168.
GIRK channel: recombinant ai-3 stimulated atrial K+ channels PMID:2535845. Note:
the field subsequently attributed GIRK activation mainly to Gbetagamma; this alpha-subunit claim is
historical and not used for a core-function term.
TRPC5: direct Gai3 effector with cryo-EM structure PMID:37137991 and ["Electrophysiological analysis shows that Gαi3 increases
the sensitivity of TRPC5 to phosphatidylinositol 4,5-bisphosphate (PIP2)"]. No GOA row captures an
ion-channel-regulator MF; left as a suggested question rather than a NEW row.

GIV is a non-receptor GEF for Gai PMID:19211784.
Gai-GIV-EGFR complex PMID:20462955.
Membrane recruitment of GIV activates Gai3 PMID:27864364.
DAPLE links Frizzled to Gai PMID:26126266.
PLCD4b GBA motif PMID:30194280
GoLoco/GPR proteins (GPSM1/AGS3, GPSM2/LGN, GPSM3, PCP2, RGS14) bind GDP-Gai3 (UniProt SUBUNIT;
numerous binary-interactome IPI rows). These partner interactions are real but the generic
protein binding rows are uninformative; all 17 were REMOVEd per project policy.

Centrosome / midbody PMID:17635935. Caveat from full text: "Giα1 and Giα2 localized in the centrosomes of
interphase and mitotic cells, but Giα3 did not, contrary to what we observed with Giα3-YFP" (endogenous
antibody failed; YFP fusion positive). Midbody endogenous staining: "We also detected midbody Giα3 and
RGS14 staining". Overexpression phenotype: "Both wild-type and the GTPase-deficient form of Giα3
resulted in prolonged mitosis, although they did not affect cytokinesis." Treated as non-core.
Plasma membrane predominant for YFP fusions PMID:17635935.
Golgi: older literature cited in PMID:17635935: "(1994) reported strong plasma membrane and Golgi staining
by an anti-Giα3 antibody in certain cells."
Macroautophagy (HT-29 cells) PMID:12642577 Abstract only; nucleotide-state dependent (GDP-bound form promotes,
GTP-bound form was earlier shown to inhibit). Kept as non-core.

Auriculocondylar syndrome 1 (ARCND1), dominant missense (e.g. G40R in G1 motif) PMID:22560091 and
["We suggest that PLCB4 and GNAI3 are core signaling molecules of the endothelin-1-distal-less homeobox
5 and 6 (EDN1-DLX5/DLX6) pathway."]; additional case PMID:23315542. Interesting mechanistically: a Gi alpha in an EDNRA (Gq-coupled) pathway; dominant
interference proposed.

smFRET of the alpha-helical domain (AHD) opening in muOR-Gi complexes. Methods state the protein used
was Gai1, not Gai3: "The R90C and E238C substitutions were introduced into a previously published
minimal cysteine background (C3S;C66A;C214S;C350S;C325A;C351I) of human Gαi1" and "WT Gi heterotrimer
(Gαi1β1γ2) from Hi-5 cells was prepared similarly". Because no Gai3 was assayed, it is NOT cited in
the GNAI3 review; it is relevant to the shared Gai-family mechanism only.

Core: G protein activity / GTPase activity, GTP/GDP binding, Gbetagamma binding, heterotrimeric
G-protein complex at the cytoplasmic side of the plasma membrane, adenylate cyclase-inhibiting GPCR
signaling.
General pathway terms (GPCR signaling pathway, adenylate cyclase-modulating, signal transduction) MODIFY
to the adenylate cyclase-inhibiting pathway; generic membrane MODIFY to plasma membrane;
guanyl nucleotide binding MODIFY to GTP binding.
GTP metabolic process marked over-annotated (GTP hydrolysis by a signaling switch is not a metabolic
role).
Intracellular localizations (centrosome, midbody, Golgi, ER, lysosome, exosome, cytoplasm, cytosol),
cell division and macroautophagy regulation kept as non-core.