Gpr161
entrez
240888
canonical
uniprot
B2RPY5
canonical
ensembl
ENSMUSG00000040836
resolver
ensp
ENSMUSP00000107077
resolver
ensp
ENSMUSP00000136621
resolver
ensp
ENSMUSP00000251853
resolver
ensp
ENSMUSP00000251854
resolver
ensp
ENSMUSP00000251855
resolver
enst
ENSMUST00000111450
resolver
genesymbol
Gpr161
resolver
genesymbol_syn
Gm208
resolver
uniprot
A0A140T8Q9
resolver
uniprot
B0L0L8
resolver
uniprot
J3QN69
resolver
uniprot
Q80T48
resolver
uniprot_entry
A0A140T8Q9_MOUSE
resolver
uniprot_entry
GP161_MOUSE
resolver
uniprot_sec
B0L0L8
resolver
uniprot_sec
J3QN69
resolver
uniprot_sec
Q80T48
resolver
activity_regulation
ACTIVITY REGULATION: In contrast to the majority of G protein-coupled receptors, it is not activated by a ligand and it either acts as a constitutively active receptor or as a mechanosensitive receptor (PubMed:23332756, PubMed:40737401). Cholesterol promotes coupling to G(s)/GNAS and G protein-coupled receptor activity (By similarity). {ECO:0000250|UniProtKB:Q8N6U8, ECO:0000269|PubMed:23332756, ECO:0000269|PubMed:40737401}.
uniprot
proteins
amino_acid_sequence
MDFVQHALLTASRGALTMSLNSSLSYRKELSNLTATEGGEGGAVSEFIAIIIITVLVCLGNLVIVVTLYKKSYLLTLSNKFVFSLTLSNFLLSVLVLPFVVTSSIRREWIFGVVWCNFSALLYLLISSASMLTLGVIAIDRYYAVLYPMVYPMKITGNRAVMALVYIWLHSLIGCLPPLFGWSSVEFDEFKWMCVAAWHQEPGYTIFWQIWCALFPFLIMLVCYGFIFRVARVKARKVHCGTVVTVEEDSQRSGRKNSSTSTSSSGSRRNALQGVVYSANQCKALITILVVIGAFMVTWGPYMVVITSEALWGKNCVSPTLETWATWLSFTSAICHPLIYGLWNKTVRKELLGMCFGDRYYRESFVQRQRTSRLFSISNRITDLGLSPHLTALMAGGQSLGHSSSTGDTGFSYSQDSGTDVMLLEDGTSEDNPPQHCTCPPKRRSSVTFEDEVEQIKEAAKNSLLHVKAEVHKSLDSYAASLAKAIEAEAKINLFGEEALPGVLFTARTVPGAGFGGRRGSRTLVNQRLQLQSIKEGNVLAAEQR
uniprot
proteins
disease_involvement
DISEASE: Note=An intragenic deletion in Gpr161 is responsible for the vacuolated lens (vl) phenotype that is characterized by neural tube defects and congenital cataracts. The vl mutation aroses spontaneously. About half of vl/vl embryos display lumbar-sacral spina bifida and die before birth, and the other half have closed neural tubes but show thinning of the midline neuroepithelium and epidermis, dilation of the dorsal ventricle, and presence of ectopic neuroepithelial cells in the ventricle. All surviving adults display congenital cataracts (PubMed:18250320). It is not a null mutant allele (PubMed:23332756). {ECO:0000269|PubMed:18250320, ECO:0000269|PubMed:23332756}.
uniprot
proteins
function
FUNCTION: G protein-coupled receptor that acts as a key inhibitor of the smoothened signaling pathway in primary cilia (PubMed:23332756, PubMed:27357676, PubMed:29386106, PubMed:34346313, PubMed:38326651, PubMed:40737401). Inhibits the smoothened signaling pathway in absence of hedgehog (DHH, IHH or SHH) by promoting formation of the transcription repressor form of GLI2 and GLI3 transcription factors (PubMed:23332756, PubMed:27357676, PubMed:29386106, PubMed:34346313, PubMed:40737401). GPR161 activation triggers signaling via guanine nucleotide-binding protein G(s)/GNAS, mediating activation of adenylate cyclase activity and production of cAMP (PubMed:23332756, PubMed:34346313, PubMed:40737401). Increased cAMP levels activate PKA, promoting PKA-dependent processing of GLI2 and GLI3 transcription factors, leading to formation of transcription repressor GLI2R and GLI3R, which repress expression of target genes (PubMed:23332756). GPR161 also activates PKA by acting as a PKA-anchoring protein, which directly associates with type I PKA regulatory subunits (PRKAR1A and/or PRKAR1B), recruiting PKA followed by PKA-dependent processing of GLI2 and GLI3 transcription factors (PubMed:27357676, PubMed:38326651). In presence of hedgehog, GPR161 is removed from primary cilia by smoothened (SMO), preventing its activity and allowing activation of the smoothened signaling (PubMed:23332756). In contrast to the majority of G protein-coupled receptors, it is not activated by a ligand and it either acts as a constitutively active receptor or as a mechanosensitive receptor (PubMed:23332756, PubMed:40737401). Involved in regulation of the smoothened signaling pathway during early neural tube development, forelimb formation, skeletal development, embryonic cerebellar development and forebrain development (PubMed:18250320, PubMed:29222391, PubMed:29386106, PubMed:30914320). Involved in the saltatory migration of neurons during brain development by acting as a mechanosensitive receptor that senses mechanical forces generated by fluid shear stress (PubMed:40737401). {ECO:0000269|PubMed:18250320, ECO:0000269|PubMed:23332756, ECO:0000269|PubMed:27357676, ECO:0000269|PubMed:29222391, ECO:0000269|PubMed:29386106, ECO:0000269|PubMed:30914320, ECO:0000269|PubMed:34346313, ECO:0000269|PubMed:38326651, ECO:0000269|PubMed:40737401}.
uniprot
proteins
mass_dalton
60303
uniprot
proteins
mutagenesis
MUTAGEN 145; /note="V->E: Inactive mutant unable to increase cAMP upon induction."; /evidence="ECO:0000269|PubMed:23332756"; MUTAGEN 233..237; /note="VKARK->AAAA: Abolished localization to cilium. Mutant knockin mice display high smoothened signaling and polydactyly in limb buds. Knockin mice show embryonic lethality by 14.5 days post coitum (dpc)."; /evidence="ECO:0000269|PubMed:34346313"; MUTAGEN 233..237; /note="VKARK->AAAAA: In mut1; abolishes localization to primary cilia."; /evidence="ECO:0000269|PubMed:23332756"; MUTAGEN 238..241; /note="VHCG->AAAA: In mut2; weakly affects localization to primary cilia."; /evidence="ECO:0000269|PubMed:23332756"; MUTAGEN 243..244; /note="VV->AA: In mut3; does not affect localization to primary cilia; when associated with A-251."; /evidence="ECO:0000269|PubMed:23332756"; MUTAGEN 251; /note="Q->A: In mut3; does not affect localization to primary cilia; when associated with 243-A-A-244."; /evidence="ECO:0000269|PubMed:23332756"; MUTAGEN 254..257; /note="GRKN->AAAA: In mut4; does not affect localization to primary cilia."; /evidence="ECO:0000269|PubMed:23332756"; MUTAGEN 258..262; /note="SSTST->ASAAA: In mut5; does not affect localization to primary cilia."; /evidence="ECO:0000269|PubMed:23332756"; MUTAGEN 344..355; /note="Missing: In GPR161H8del mutant; knockin mice show defects in saltatory migration of neurons."; /evidence="ECO:0000269|PubMed:40737401"; MUTAGEN 445..446; /note="SS->AA: Abolished phosphorylation by PKA; does not affect localization to cilium."; /evidence="ECO:0000269|PubMed:27357676"; MUTAGEN 445..446; /note="SS->DD: Mimics phosphorylation; impaired localization to cilium."; /evidence="ECO:0000269|PubMed:27357676"; MUTAGEN 482; /note="L->P: Abolished interaction with PRKAR1A or PRKAR1B."; /evidence="ECO:0000269|PubMed:27357676
uniprot
proteins
post_translational_modification
PTM: Phosphorylated by GRK2 in presence of smoothened (SMO), promoting association with beta-arrestin (ARRB1 or ARRB2), and export from primary cilia by the BBSome and IFT-B complexes. {ECO:0000250|UniProtKB:Q8N6U8}.
uniprot
proteins
protein_family
G protein-coupled receptor 1 family
uniprot
proteins
pubmed
12679517
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
18250320
uniprot
proteins
pubmed
19468303
uniprot
proteins
pubmed
23332756
uniprot
proteins
pubmed
27357676
uniprot
proteins
pubmed
29222391
uniprot
proteins
pubmed
29386106
uniprot
proteins
pubmed
30914320
uniprot
proteins
pubmed
34346313
uniprot
proteins
pubmed
38326651
uniprot
proteins
pubmed
40737401
uniprot
proteins
sequence_length
545
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell projection, cilium membrane {ECO:0000269|PubMed:23332756, ECO:0000269|PubMed:27357676, ECO:0000269|PubMed:34346313, ECO:0000269|PubMed:38326651, ECO:0000269|PubMed:40737401}; Multi-pass membrane protein {ECO:0000255}. Cell membrane {ECO:0000269|PubMed:23332756, ECO:0000269|PubMed:38326651}; Multi-pass membrane protein {ECO:0000255}. Note=Recruited to primary cilium in a TULP3 and IFT-A complex-dependent manner (PubMed:23332756, PubMed:34346313). In presence of smoothened (SMO), it is removed from primary cilia and is internalized into recycling endosomes and is apparently not degraded (PubMed:23332756). Export from primary cilia is mediated via a beta-arrestin, BBSome and IFT-B complex-dependent mechanism (By similarity). {ECO:0000250|UniProtKB:Q8N6U8, ECO:0000269|PubMed:23332756, ECO:0000269|PubMed:34346313}.
uniprot
proteins
transmembrane_region
TRANSMEM 48..71; /note="Helical; Name=1"; /evidence="ECO:0000250|UniProtKB:Q8N6U8"; TRANSMEM 75..97; /note="Helical; Name=2"; /evidence="ECO:0000250|UniProtKB:Q8N6U8"; TRANSMEM 122..142; /note="Helical; Name=3"; /evidence="ECO:0000250|UniProtKB:Q8N6U8"; TRANSMEM 156..174; /note="Helical; Name=4"; /evidence="ECO:0000250|UniProtKB:Q8N6U8"; TRANSMEM 208..228; /note="Helical; Name=5"; /evidence="ECO:0000250|UniProtKB:Q8N6U8"; TRANSMEM 284..303; /note="Helical; Name=6"; /evidence="ECO:0000250|UniProtKB:Q8N6U8"; TRANSMEM 324..343; /note="Helical; Name=7"; /evidence="ECO:0000250|UniProtKB:Q8N6U8
uniprot
proteins