GNAI3 encodes Gi alpha-3, the alpha subunit of the pertussis toxin-sensitive Gi3 heterotrimeric G protein. It is a 354-residue, N-terminally lipid-anchored GTPase of the G(i/o/t/z) subfamily that sits on the cytoplasmic face of the plasma membrane in complex with a Gbeta-gamma dimer. Agonist-bound Gi/o-coupled receptors catalyse GDP-to-GTP exchange on GNAI3; GTP-bound GNAI3 dissociates from Gbeta-gamma and inhibits adenylyl cyclase, lowering cAMP, and can directly activate effectors such as the TRPC5 cation channel. Intrinsic GTP hydrolysis, accelerated by RGS-domain GAPs (e.g. RGS10, RGS16), terminates signaling. GNAI3 is also activated outside receptors by GBA-motif guanine nucleotide exchange factors (GIV/Girdin, DAPLE, PLCD4) that couple growth factor and Wnt-Frizzled signaling to Gi, and its GDP-bound form is bound by GoLoco-motif proteins (GPSM1/AGS3, GPSM2/LGN, GPSM3, RGS14). Intracellular pools at the Golgi, centrosome and midbody have been implicated in macroautophagy control and cell division. Dominant missense variants (e.g. p.Gly40Arg in the G1 motif) cause auriculocondylar syndrome 1, a craniofacial malformation attributed to disrupted endothelin-1-DLX5/6 signaling in mandibular development.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IDA PMID:12642577 The G-protein regulator AGS3 controls an early event during ... | KEEP AS NON CORE | Summary: GNAI3 colocalizes with Golgi membranes in HT-29 intestinal cells, in the context of AGS3/Gai3 control of macroautophagy. Reason: Gai3 has been reported on Golgi membranes, although earlier antibody staining was inconsistent between cell types (as discussed in PMID:17635935), and the curator's colocalizes_with qualifier appropriately limits the claim. The cached paper is abstract-only, so I defer to the curator. Golgi association is a secondary, non-canonical location relative to the plasma membrane heterotrimer. Supporting Evidence: PMID:12642577 Both the endogenous form of AGS3 and a tagged expressed form have a localization compatible with a role in the Galphai3-dependent control of autophagy. |
| GO:0003924 GTPase activity | IDA PMID:19478087 Structural determinants of G-protein alpha subunit selectivi... | ACCEPT | Summary: GTPase activity of GNAI3, assayed in the context of RGS-accelerated GTP hydrolysis of Gai subunits. Reason: Intrinsic GTPase activity terminating the active state is the defining catalytic activity of Galpha subunits. Gai3 GTP hydrolysis is directly accelerated by RGS GAPs (RGS10, RGS16, RGS8); the curator's IDA from the full text is consistent with this. Supporting Evidence: PMID:19478087 a trio of point mutations to RGS2 that elicits Galpha(i)-directed binding and GAP activities PMID:8774883 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. |
| GO:0003924 GTPase activity | IEA GO_REF:0000120 | ACCEPT | Summary: InterPro/ARBA-based assignment of GTPase activity from the G-alpha domain. Reason: Correct; GNAI3 retains the G1-G5 motifs of the G-alpha domain and has experimentally demonstrated, RGS-accelerated GTP hydrolysis. Supporting Evidence: PMID:8774883 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. |
| GO:0003924 GTPase activity | TAS PMID:3109953 Molecular cloning of a new human G protein. Evidence for two... | ACCEPT | Summary: Traceable author statement from the original cDNA cloning of GNAI3 (as 'Gx alpha') from HL-60 cells. Reason: The cloning paper itself only establishes sequence relatedness to Gi alpha, but GTPase activity is well established for Gai3 by later biochemistry (RGS10 GAP assays). The claim is correct and core. Supporting Evidence: PMID:3109953 The cDNA encodes a polypeptide of 354 amino acids (Mr 40,519) which is closely related to Gi alpha proteins. PMID:8774883 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. |
| GO:0003925 G protein activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA assignment of G protein activity (GTP/GDP-cycling switch that engages effectors in the GTP-bound state) to the Galpha family node. Reason: This is the most informative molecular function term for GNAI3: it cycles between GDP-bound inactive heterotrimer and GTP-bound active Galpha that regulates effectors (adenylyl cyclase inhibition, TRPC5 activation). GNAI3 sits well within the Gi/o clade from which the IBD was propagated. Supporting Evidence: file:human/GNAI3/GNAI3-uniprot.txt The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. PMID:37137991 Here, we present the cryo-electron microscopy structures of the human transient receptor potential canonical 5 (TRPC5)-GΞ±i3 complexes with a 4:4 stoichiometry in lipid nanodiscs. |
| GO:0005515 protein binding | IPI PMID:18434541 Structural diversity in the RGS domain and its interaction w... | REMOVE | Summary: IPI with RGS10 from a structural survey of RGS domain/Galpha complexes; RGS10 is a GAP for Gai3. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:18434541 RGS domain binding consequently accelerates Galpha-mediated GTP hydrolysis. PMID:8774883 RGS10 associates specifically with the activated forms of two related G-protein subunits, G alphai3, and G alphaz |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: Yeast two-hybrid interaction with RGS14 from a human liver interactome screen. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Binary interactome (HI-II-14) interaction with RGS17, an RGS-domain GAP. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Binary interactome (HI-II-14) interaction with GPSM3, a GoLoco-motif GDI. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:26126266 Daple is a novel non-receptor GEF required for trimeric G pr... | REMOVE | Summary: Interaction with DAPLE/CCDC88C via its GBA motif; DAPLE acts as a non-receptor GEF on Gai. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:26126266 Daple contains a GΞ±-binding and activating (GBA) motif, which activates GΞ±i proteins |
| GO:0005515 protein binding | IPI PMID:27621449 GIV/Girdin activates GΞ±i and inhibits GΞ±s via the same motif... | REMOVE | Summary: Interaction with GIV/Girdin (CCDC88A) GBA motif, which activates Gai. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: BioPlex affinity-purification interaction with PCP2, a GoLoco-motif protein. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:30194280 A biochemical and genetic discovery pipeline identifies PLCΞ΄... | REMOVE | Summary: Interaction with PLCD4 isoform a GBA motif, identified in a GBA-motif discovery pipeline using Gai3. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:30194280 putative GBA motifs discovered in bioinformatics searches were synthesized on peptide arrays and probed in batch for GΞ±i3 binding. |
| GO:0005515 protein binding | IPI PMID:30194280 A biochemical and genetic discovery pipeline identifies PLCΞ΄... | REMOVE | Summary: Interaction with PLCD4 isoform b (PLCdelta4b) GBA motif, which acts as a non-receptor GEF. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:30194280 putative GBA motifs discovered in bioinformatics searches were synthesized on peptide arrays and probed in batch for GΞ±i3 binding. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interactome (HuRI) interaction with RGS14. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interactome (HuRI) interaction with GPSM2/LGN, a GoLoco-motif protein. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interactome (HuRI) interaction with PCP2. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interactome (HuRI) interaction with PHF24. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interactome (HuRI) interaction with GPSM3. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Interactome (BioPlex dual cell line) interaction with RGS14. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Multimodal cell map interaction with RGS14. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Multimodal cell map interaction with GPSM2/LGN. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Multimodal cell map interaction with GPSM3. Reason: Generic protein binding is uninformative about function. The interaction itself is not disputed: GNAI3 is engaged by many regulators (RGS-domain GAPs, GoLoco/GPR-motif GDIs such as GPSM1-3, PCP2 and RGS14, and GBA-motif non-receptor GEFs such as GIV/CCDC88A, DAPLE/CCDC88C and PLCD4). These regulator relationships are captured in the description and core functions (G protein activity) rather than as a bare protein binding annotation. Removal does not mean the reported interaction is false. |
| GO:0005525 GTP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based GTP binding. Reason: GTP binding by the G-alpha nucleotide pocket is required for the active state and is core to GNAI3 function. Supporting Evidence: file:human/GNAI3/GNAI3-uniprot.txt The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA assignment of cytoplasm (is_active_in) from the Galpha family. Reason: Galpha subunits are cytoplasmic peripheral proteins anchored to the inner leaflet of membranes; the cytoplasm term is correct but the functionally relevant location is the cytoplasmic side of the plasma membrane, which is accepted separately. Supporting Evidence: PMID:17635935 Imaging of live cells transfected with the GiΞ±-YFP constructs demonstrated that the fusion proteins were predominantly localized at the plasma membrane in most cells, although not in all cells |
| GO:0005737 cytoplasm | IDA PMID:17635935 Localization of Gi alpha proteins in the centrosomes and at ... | KEEP AS NON CORE | Summary: YFP-tagged Gai proteins were observed in cytoplasm as well as at the plasma membrane and centrosomes in HeLa cells. Reason: Correct, as GNAI3 is a peripheral membrane protein with a cytoplasmic pool, but the cytoplasm is not where its core signaling function is executed. Supporting Evidence: PMID:17635935 Imaging of live cells transfected with the GiΞ±-YFP constructs demonstrated that the fusion proteins were predominantly localized at the plasma membrane in most cells, although not in all cells |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic transfer of cytoplasm localization from mouse ortholog and UniProt subcellular location mapping. Reason: Correct but peripheral; GNAI3 acts mainly at the cytoplasmic face of the plasma membrane. |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | KEEP AS NON CORE | Summary: Detected by mass spectrometry in membranes purified from placental lysosomes. Reason: High-throughput organelle proteomics; peripheral lipid-anchored proteins such as Galpha subunits frequently co-purify with organelle membranes. No targeted study places GNAI3 function at lysosomes, though Gai3 has been linked to control of lysosomal-autophagic catabolism. Kept as non-core rather than removed since the data are real. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:12642577 The G-protein regulator AGS3 controls an early event during ... | KEEP AS NON CORE | Summary: Colocalization of GNAI3 with ER membranes in HT-29 cells (AGS3/macroautophagy study). Reason: Abstract-only paper; the curator's colocalizes_with qualifier appropriately limits the claim. Intracellular membrane pools of Gai3 are plausible but peripheral to its plasma membrane signaling function. Supporting Evidence: PMID:12642577 Both the endogenous form of AGS3 and a tagged expressed form have a localization compatible with a role in the Galphai3-dependent control of autophagy. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer of Golgi apparatus localization from the mouse ortholog via Ensembl Compara. Reason: Consistent with the IDA Golgi membrane colocalization row for human GNAI3 (PMID:12642577), which keeps the organelle claim; antibody-staining reports of Golgi Gai3 vary between cell types, so the location is non-core. Supporting Evidence: PMID:12642577 Both the endogenous form of AGS3 and a tagged expressed form have a localization compatible with a role in the Galphai3-dependent control of autophagy. |
| GO:0005813 centrosome | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Human Protein Atlas immunofluorescence localization to the centrosome. Reason: Consistent with YFP-fusion data showing Gai3 at centrosomes; a receptor-independent intracellular pool of uncertain functional significance. Non-core. |
| GO:0005813 centrosome | IDA PMID:17635935 Localization of Gi alpha proteins in the centrosomes and at ... | KEEP AS NON CORE | Summary: Gai3-YFP colocalized with pericentrin at centrosomes in HeLa cells; endogenous Gai3 was not detected there with the antibody used. Reason: The localization rests on an overexpressed YFP fusion (and a prior report cited by the authors); the endogenous-antibody result was negative, which the authors attribute to detection limits. Centrosomal Gai is linked to RGS14/LGN-regulated cell division but is not GNAI3's core function. Supporting Evidence: PMID:17635935 GiΞ±2- and GiΞ±3-YFP also targeted to the centrosomes, colocalizing with another centrosome marker, pericentrin, as did the GiΞ±1-YFP PMID:17635935 GiΞ±1 and GiΞ±2 localized in the centrosomes of interphase and mitotic cells, but GiΞ±3 did not, contrary to what we observed with GiΞ±3-YFP |
| GO:0005813 centrosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping (centrosome). Reason: Derived from the UniProt location statement based on PMID:17635935; see review of the IDA rows. Non-core. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Human Protein Atlas immunofluorescence localization to the cytosol. Reason: Plausible soluble pool of a peripheral membrane protein; not where the core signaling function occurs. |
| GO:0005834 heterotrimeric G-protein complex | IBA GO_REF:0000033 | ACCEPT | Summary: IBA assignment of heterotrimeric G-protein complex membership. Reason: GNAI3 is the alpha subunit of Gi3 heterotrimers (with Gbeta and Ggamma); heterotrimer formation is the basis of its receptor coupling. Core. Supporting Evidence: file:human/GNAI3/GNAI3-uniprot.txt GTP binding causes dissociation of the heterotrimer, liberating the individual subunits so that they can interact with downstream effector proteins. Reactome:R-HSA-380073 This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein. |
| GO:0005886 plasma membrane | EXP PMID:17635935 Localization of Gi alpha proteins in the centrosomes and at ... | ACCEPT | Summary: Gai3-YFP was predominantly localized at the plasma membrane in live HeLa cells. Reason: Plasma membrane is the principal site of GNAI3 action as part of receptor-coupled heterotrimers. Supporting Evidence: PMID:17635935 Imaging of live cells transfected with the GiΞ±-YFP constructs demonstrated that the fusion proteins were predominantly localized at the plasma membrane in most cells, although not in all cells |
| GO:0005886 plasma membrane | IDA PMID:27864364 Membrane Recruitment of the Non-receptor Protein GIV/Girdin ... | ACCEPT | Summary: Gai3 detected on membranes in cell fractionation/biosensor experiments with GIV. Reason: GIV activates Gai3 only when recruited to membranes where its substrate Gai3 resides; the plasma membrane location of Gai3 is core. Supporting Evidence: PMID:27864364 We found that in unstimulated cells GIV does not co-fractionate with its substrate G protein GΞ±i3 on cell membranes |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (cell membrane). Reason: Correct and core; supported experimentally (PMID:17635935, PMID:27864364). Supporting Evidence: file:human/GNAI3/GNAI3-uniprot.txt Cell membrane {ECO:0000269|PubMed:17635935, ECO:0000269|PubMed:27864364}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-170666 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-170671 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-170674 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-170686 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-380073 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. Supporting Evidence: Reactome:R-HSA-380073 This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-392187 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-392195 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-392202 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749454 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749456 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-751001 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8964242 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8964329 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982012 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982019 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8982020 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9021600 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9021601 | ACCEPT | Summary: Reactome TAS: Gi heterotrimer reactions occur at the plasma membrane. Reason: Reactome places Gi alpha (including GNAI3) at the plasma membrane in its heterotrimeric G protein (Gi) reactions, where it is activated by liganded GPCRs, regulated by RGS proteins and reassociates with Gbetagamma. This is the canonical site of action of GNAI3, supported experimentally for this gene by live-cell imaging. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based signal transduction from the Galpha insert domain. Reason: True but far too general; GNAI3 transduces GPCR signals by inhibiting adenylyl cyclase, which is captured by the adenylate cyclase-inhibiting GPCR signaling pathway term (also annotated by IDA). Proposed replacements: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway Supporting Evidence: file:human/GNAI3/GNAI3-uniprot.txt Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based GPCR signaling pathway. Reason: Correct but general; the specific pathway supported for GNAI3 is the adenylate cyclase-inhibiting GPCR signaling pathway (IDA, PMID:19478087; TAS, PMID:7608168). Proposed replacements: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway Supporting Evidence: PMID:7608168 We found that both the chick and human m2 mAChRs can couple to Gi alpha-1, Gi alpha-2, Gi alpha-3, and G(o)alpha |
| GO:0007188 adenylate cyclase-modulating G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | MODIFY | Summary: IBA assignment of adenylate cyclase-modulating GPCR signaling to the Galpha family node. Reason: Correct at the family level, but for Gi-class alpha subunits the modulation is specifically inhibitory. The more specific descendant GO:0007193 is already annotated to GNAI3 (IDA) and is the appropriate term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000026392 Β· PTN000026392 SUPPORTS TRANSFER The IBD node spans Galpha subunits of both signs (Gs-class stimulatory and Gi-class inhibitory donors), so the shared assertion is pitched at adenylate cyclase-modulating. The transfer to GNAI3 is correct; only the granularity is coarser than the gene-specific evidence (IDA for the inhibiting pathway). Proposed replacements: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway Supporting Evidence: PMID:7608168 We found that both the chick and human m2 mAChRs can couple to Gi alpha-1, Gi alpha-2, Gi alpha-3, and G(o)alpha file:human/GNAI3/GNAI3-uniprot.txt Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels |
| GO:0007188 adenylate cyclase-modulating G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based adenylate cyclase-modulating GPCR signaling. Reason: Correct but general; GNAI3 is a Gi-class alpha subunit that inhibits adenylyl cyclase, so the specific descendant GO:0007193 (already annotated) is preferred. Proposed replacements: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway Supporting Evidence: PMID:7608168 We found that both the chick and human m2 mAChRs can couple to Gi alpha-1, Gi alpha-2, Gi alpha-3, and G(o)alpha |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IDA PMID:19478087 Structural determinants of G-protein alpha subunit selectivi... | ACCEPT | Summary: Gai inhibition of adenylyl cyclase / cAMP accumulation assessed in the RGS2 selectivity study. Reason: Inhibition of adenylyl cyclase downstream of Gi-coupled receptors is the canonical signaling output of GNAI3 (UniProt: 'Inhibits adenylate cyclase activity'), and m2 muscarinic receptors couple to AC inhibition through Gai3. Core process. Supporting Evidence: file:human/GNAI3/GNAI3-uniprot.txt Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels PMID:7608168 We found that both the chick and human m2 mAChRs can couple to Gi alpha-1, Gi alpha-2, Gi alpha-3, and G(o)alpha |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA-based adenylate cyclase-inhibiting GPCR signaling pathway. Reason: Correct and core; consistent with the IDA annotation. Supporting Evidence: PMID:7608168 We found that both the chick and human m2 mAChRs can couple to Gi alpha-1, Gi alpha-2, Gi alpha-3, and G(o)alpha |
| GO:0007194 negative regulation of adenylate cyclase activity | TAS PMID:7608168 Differential coupling of m2 and m4 muscarinic receptors to i... | ACCEPT | Summary: m2 muscarinic receptors couple to inhibition of adenylyl cyclase through Gai3 in reconstitution experiments. Reason: GTP-bound Gai3 directly inhibits adenylyl cyclase; the term describes the regulatory outcome of GNAI3 activity and is core. Supporting Evidence: PMID:7608168 We found that both the chick and human m2 mAChRs can couple to Gi alpha-1, Gi alpha-2, Gi alpha-3, and G(o)alpha |
| GO:0009898 cytoplasmic side of plasma membrane | IDA PMID:17635935 Localization of Gi alpha proteins in the centrosomes and at ... | ACCEPT | Summary: Gai3-YFP localized predominantly at the plasma membrane; Galpha subunits are lipid-anchored to the inner leaflet. Reason: The most precise location term for GNAI3 signaling: an N-terminally lipid-anchored peripheral protein on the cytoplasmic face of the plasma membrane. Supporting Evidence: PMID:17635935 Imaging of live cells transfected with the GiΞ±-YFP constructs demonstrated that the fusion proteins were predominantly localized at the plasma membrane in most cells, although not in all cells |
| GO:0009898 cytoplasmic side of plasma membrane | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA-based cytoplasmic side of plasma membrane. Reason: Correct and core; consistent with the lipid-anchored heterotrimer location. Supporting Evidence: file:human/GNAI3/GNAI3-uniprot.txt Cell membrane {ECO:0000269|PubMed:17635935, ECO:0000269|PubMed:27864364}; |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MODIFY | Summary: Detected in the membrane proteome of the YTS NK-like cell line. Reason: Correct but uninformative; the specific membrane for GNAI3 is the plasma membrane (accepted elsewhere in this review). Proposed replacements: plasma membrane |
| GO:0016239 positive regulation of macroautophagy | IMP PMID:12642577 The G-protein regulator AGS3 controls an early event during ... | KEEP AS NON CORE | Summary: In HT-29 cells, Gai3 (in its GDP-bound state stabilized by AGS3) promotes an early step of macroautophagy. Reason: Abstract-only in cache; the curator's IMP is accepted. Note the effect is nucleotide-state dependent (GDP-Gai3 stimulatory; GTP-Gai3 was earlier reported to inhibit autophagy in the same system), so GNAI3 is better described as regulating macroautophagy. This is a cell-type-specific, non-canonical role. Supporting Evidence: PMID:12642577 AGS3 contains GoLoco or G-protein regulatory motifs in its COOH-terminal half that stabilize the GDP-bound conformation of the alpha-subunit of the trimeric Gi3 protein. The latter is part of a signaling pathway that controls the lysosomal-autophagic catabolism in human colon cancer HT-29 cells. |
| GO:0019001 guanyl nucleotide binding | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based guanyl nucleotide binding. Reason: Correct but general; GNAI3 binds both GTP and GDP. GTP binding (also annotated) is the more informative child. Proposed replacements: GTP binding Supporting Evidence: file:human/GNAI3/GNAI3-uniprot.txt The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. |
| GO:0019003 GDP binding | IDA PMID:19478087 Structural determinants of G-protein alpha subunit selectivi... | ACCEPT | Summary: GDP binding of Gai assayed in the RGS2 selectivity study. Reason: GDP-bound Gai3 is the inactive heterotrimer-competent state and the substrate for GEFs (GPCRs, GIV, DAPLE) and GoLoco GDIs; GDP binding is core to the switch mechanism. Supporting Evidence: file:human/GNAI3/GNAI3-uniprot.txt The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. PMID:12642577 AGS3 contains GoLoco or G-protein regulatory motifs in its COOH-terminal half that stabilize the GDP-bound conformation of the alpha-subunit of the trimeric Gi3 protein. The latter is part of a signaling pathway that controls the lysosomal-autophagic catabolism in human colon cancer HT-29 cells. |
| GO:0030496 midbody | IDA PMID:17635935 Localization of Gi alpha proteins in the centrosomes and at ... | KEEP AS NON CORE | Summary: Endogenous Gai3 staining at the midbody of dividing cells. Reason: Real but non-canonical intracellular localization during cytokinesis. Supporting Evidence: PMID:17635935 We also detected midbody GiΞ±3 and RGS14 staining |
| GO:0030496 midbody | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA-based midbody localization. Reason: Consistent with the IDA evidence; non-core. |
| GO:0031683 G-protein beta/gamma-subunit complex binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based Gbetagamma complex binding. Reason: Binding of the Gbetagamma dimer by GDP-bound Gai3 forms the heterotrimer that receptors activate, and Gbetagamma release upon activation mediates part of Gi signaling. Core. Supporting Evidence: file:human/GNAI3/GNAI3-uniprot.txt GTP binding causes dissociation of the heterotrimer, liberating the individual subunits so that they can interact with downstream effector proteins. PMID:19211784 the GEF motif is capable of activating as well as sequestering the G alpha-subunit, thereby enhancing Akt signaling via the G betagamma-PI3K pathway |
| GO:0046039 GTP metabolic process | IDA PMID:19478087 Structural determinants of G-protein alpha subunit selectivi... | MARK AS OVER ANNOTATED | Summary: GTP hydrolysis by Gai assayed in the RGS2 study, annotated as GTP metabolic process. Reason: GNAI3 hydrolyses GTP as a timing mechanism for a signaling switch (captured by GTPase activity / G protein activity); it does not contribute to cellular GTP metabolism in any physiological sense. Supporting Evidence: PMID:19478087 a trio of point mutations to RGS2 that elicits Galpha(i)-directed binding and GAP activities |
| GO:0051301 cell division | IDA PMID:17635935 Localization of Gi alpha proteins in the centrosomes and at ... | KEEP AS NON CORE | Summary: Overexpressed Gai3 prolonged mitosis; combined knockdown of Gai1-3 caused cytokinesis failure in HeLa cells. Reason: Evidence is from overexpression and triple knockdown, and the authors frame the role as suggestive. A possible receptor-independent role in cell division (with RGS14/LGN regulators) is non-core. Supporting Evidence: PMID:17635935 Both wild-type and the GTPase-deficient form of GiΞ±3 resulted in prolonged mitosis, although they did not affect cytokinesis. PMID:17635935 Cells treated with pertussis toxin, with reduced expression of G(ialpha1), G(ialpha2), and G(ialpha3) or with decreased expression of RGS14 also exhibit cytokinesis defects. |
| GO:0051301 cell division | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA-based cell division. Reason: Consistent with the IDA evidence; non-core. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Detected by mass spectrometry in exosome preparations. Reason: High-throughput exosome proteomics; abundant inner-leaflet membrane proteins are commonly captured in extracellular vesicles. No known function for exosomal GNAI3. Non-core. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: Detected by mass spectrometry in exosome preparations. Reason: High-throughput exosome proteomics; abundant inner-leaflet membrane proteins are commonly captured in extracellular vesicles. No known function for exosomal GNAI3. Non-core. |
| GO:0010855 adenylate cyclase inhibitor activity | IDA PMID:8119955 Distinct patterns of bidirectional regulation of mammalian a... | NEW | Summary: Purified, activated Gi alpha 3 directly inhibits membrane adenylyl cyclases, most potently types V and VI (PMID:8119955). Reason: GTP-bound GΞ±i3 is itself the effector-regulating entity: the reconstitution assays add purified Gi alpha 3 to cyclase-containing membranes and measure reduced catalytic activity, so the inhibitor activity is performed by GNAI3. Comparator check: human GNAI1 carries GO:0010855 by IDA from the same paper, which reports Gi alpha 1, 2 and 3 alike, and mouse Gnaz carries it by IMP. This MF is the effector activity underlying the accepted adenylate cyclase-inhibiting GPCR signaling pathway (GO:0007193, IDA) row. Supporting Evidence: PMID:8119955 Types V and VI adenylyl cyclase are most sensitive to inhibition by Gi alpha 1, Gi alpha 2, and Gi alpha 3 |
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Download this section (compressed HTML)Q: Should the direct, structurally characterized activation of TRPC5 by GTP-bound GNAI3 be captured as an ion channel regulator molecular function on GNAI3 (as a G protein effector relationship), and if so which GO term best expresses an activated Galpha acting on a channel?
Q: Which Gai isoform-specific functions, if any, distinguish GNAI3 from GNAI1 and GNAI2 in vivo, given the high sequence identity and frequent compensatory up-regulation of Gai1 after Gai3 loss?
Q: How does a Gi-class alpha subunit variant (p.Gly40Arg) disrupt the endothelin-1/EDNRA-DLX5/6 pathway in auriculocondylar syndrome: dominant-negative sequestration of Gbeta-gamma or receptors, or a gain-of-function Gi signal?
Q: Do non-receptor GBA-motif GEFs (GIV, DAPLE, PLCD4) activate GNAI3 at the plasma membrane only, or also on intracellular membranes such as the Golgi and endosomes?
Experiment: Knock-in of the ARCND1 GNAI3 p.Gly40Arg variant in cranial neural crest-derived cells or mouse, with BRET biosensors of Gi activation, Gbeta-gamma release and EDNRA-Gq signaling, plus DLX5/DLX6 expression readouts.
Hypothesis: GNAI3 G40R acts as a dominant-interfering Galpha that blunts endothelin-1-driven DLX5/6 induction in the mandibular arch.
Experiment: Isoform-selective CRISPR knockouts of GNAI1, GNAI2 and GNAI3 in the same cell line, followed by receptor-panel cAMP inhibition assays and live imaging of mitosis/cytokinesis.
Hypothesis: GNAI3 contributes non-redundantly to specific receptor-AC coupling and to mitotic timing, independent of Gai1/Gai2 compensation.
Experiment: Electrophysiology of TRPC5 in cells expressing GNAI3 versus GNAI3 mutants unable to bind the TRPC5 ankyrin repeat edge, with Gi-coupled receptor stimulation.
Hypothesis: Receptor-activated GNAI3 directly sensitizes TRPC5 to PIP2 in cells, independently of Gbeta-gamma.
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