GPR161 — G Protein-Coupled Receptor 161

Migration, Crosslink

📖

GPR161 — G Protein-Coupled Receptor 161

active

wiki page Created: 2026-04-02T07:19:17 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-genes-gpr161

📖 Wiki Page

gene2976 wordssynced 2026-04-02

GPR161 — G Protein-Coupled Receptor 161

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">GPR161 — G Protein-Coupled Receptor 161</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>GPR161</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>G protein-coupled receptor 161</td>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>GPR161</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1q24.2</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>[266977](https://www.ncbi.nlm.nih.gov/gene/266977)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q9Y4X5](https://www.uniprot.org/uniprot/Q9Y4X5)</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000135547</td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>713 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~77 kDa</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Neural Tube Defects, Medulloblastoma, Alzheimer's Disease, Parkinson's Disease</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1q24.2</td>
</tr>
<tr>
<td class="label">Genomic Size</td>
<td>~15 kb</td>
</tr>
<tr>
<td class="label">Exon Count</td>
<td>12</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>713 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~77 kDa</td>
</tr>
<tr>
<td class="label">TMD Count</td>

...

GPR161 — G Protein-Coupled Receptor 161

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">GPR161 — G Protein-Coupled Receptor 161</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>GPR161</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>G protein-coupled receptor 161</td>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>GPR161</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1q24.2</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>[266977](https://www.ncbi.nlm.nih.gov/gene/266977)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q9Y4X5](https://www.uniprot.org/uniprot/Q9Y4X5)</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000135547</td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>713 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~77 kDa</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Neural Tube Defects, Medulloblastoma, Alzheimer's Disease, Parkinson's Disease</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1q24.2</td>
</tr>
<tr>
<td class="label">Genomic Size</td>
<td>~15 kb</td>
</tr>
<tr>
<td class="label">Exon Count</td>
<td>12</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>713 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~77 kDa</td>
</tr>
<tr>
<td class="label">TMD Count</td>
<td>7</td>
</tr>
<tr>
<td class="label">G Protein</td>
<td>Signaling Outcome</td>
</tr>
<tr>
<td class="label">Gαs</td>
<td>Adenylyl cyclase activation → cAMP ↑ → PKA activation</td>
</tr>
<tr>
<td class="label">Gαi</td>
<td>Not significantly coupled</td>
</tr>
<tr>
<td class="label">Gαq</td>
<td>Not significantly coupled</td>
</tr>
<tr>
<td class="label">Defect</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Exencephaly</td>
<td>Failure of cranial neural tube formation</td>
</tr>
<tr>
<td class="label">Spina bifida</td>
<td>Posterior neural tube defects</td>
</tr>
<tr>
<td class="label">Anencephaly</td>
<td>Complete failure of brain vesicle formation</td>
</tr>
<tr>
<td class="label">Cancer Type</td>
<td>GPR161 Status</td>
</tr>
<tr>
<td class="label">Basal cell carcinoma</td>
<td>Frequently lost</td>
</tr>
<tr>
<td class="label">Rhabdomyosarcoma</td>
<td>Reduced</td>
</tr>
<tr>
<td class="label">Pancreatic cancer</td>
<td>Downregulated</td>
</tr>
<tr>
<td class="label">Gliioblastoma</td>
<td>Variable</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Vismodegib</td>
<td>SMO</td>
</tr>
<tr>
<td class="label">Sonidegib</td>
<td>SMO</td>
</tr>
<tr>
<td class="label">Arising</td>
<td>SMO</td>
</tr>
<tr>
<td class="label">Component</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">PTCH1</td>
<td>Co-localization</td>
</tr>
<tr>
<td class="label">SMO</td>
<td>Inverse regulation</td>
</tr>
<tr>
<td class="label">GLI1/2/3</td>
<td>Downstream targets</td>
</tr>
<tr>
<td class="label">SUFU</td>
<td>协同抑制</td>
</tr>
<tr>
<td class="label">Variant Type</td>
<td>Example</td>
</tr>
<tr>
<td class="label">Missense</td>
<td>R384C</td>
</tr>
<tr>
<td class="label">Nonsense</td>
<td>Y556*</td>
</tr>
<tr>
<td class="label">Frameshift</td>
<td>234delC</td>
</tr>
<tr>
<td class="label">Splice site</td>
<td>IVS4+1G>A</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>Significance</td>
</tr>
<tr>
<td class="label">Ciliary localization</td>
<td>Enrichment at the ciliary tip</td>
</tr>
<tr>
<td class="label">Cilia-dependent function</td>
<td>Requires intact cilia for signaling</td>
</tr>
<tr>
<td class="label">Movement dynamics</td>
<td>Shuttles in/out of cilia with pathway activity</td>
</tr>
<tr>
<td class="label">SMO interaction</td>
<td>Inverse ciliary localization with SMO</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Agent/Approach</td>
</tr>
<tr>
<td class="label">SMO inhibitors</td>
<td>Vismodegib, Sonidegib</td>
</tr>
<tr>
<td class="label">GLI inhibitors</td>
<td>GANT-61</td>
</tr>
<tr>
<td class="label">GPR161 restoration</td>
<td>Gene therapy</td>
</tr>
<tr>
<td class="label">cAMP modulators</td>
<td>PKA inhibitors</td>
</tr>
<tr>
<td class="label">G Protein</td>
<td>Coupling Efficiency</td>
</tr>
<tr>
<td class="label">Gαs</td>
<td>High</td>
</tr>
<tr>
<td class="label">Gαi</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Gαq</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Gα12/13</td>
<td>Not detected</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Frequency</td>
</tr>
<tr>
<td class="label">rsID1</td>
<td>Variable</td>
</tr>
<tr>
<td class="label">rsID2</td>
<td>Variable</td>
</tr>
<tr>
<td class="label">rsID3</td>
<td>Rare</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Vismodegib</td>
<td>SMO</td>
</tr>
<tr>
<td class="label">Sonidegib</td>
<td>SMO</td>
</tr>
<tr>
<td class="label">Arising</td>
<td>SMO</td>
</tr>
</table>

{{.infobox .infobox-gene}}
GPR161 is a GPCR involved in Hedgehog signaling and neural tube development. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration. The receptor functions as a constitutive inhibitor of Hedgehog signaling, making it a critical regulator of developmental processes and adult tissue homeostasis. [@mukhopadhyay2013] [@chen2015]

Gene Structure and Protein Architecture

Genomic Organization

The GPR161 gene is located on chromosome 1q24.2 and consists of 12 exons spanning approximately 15 kb of genomic DNA. The gene encodes a G protein-coupled receptor with the characteristic 7-transmembrane domain architecture. The promoter region contains binding sites for multiple transcription factors including GLI proteins, creating a negative feedback loop in Hedgehog signaling. [@goodrich1996]

Protein Topology

GPR161 exhibits the classic GPCR fold:

N-terminal extracellular domain: Ligand-independent, involved in dimerization

Transmembrane domains 1-7: Form the characteristic 7TM bundle

Intracellular loops: Couple to G proteins

C-terminal cytoplasmic tail: Contains regulatory motifs

Unlike most GPCRs, GPR161 exhibits constitutive activity in the absence of any known ligand, continuously suppressing Hedgehog signaling through its basal cAMP production. [@chen2015]

Signaling Mechanism

Constitutive Hedgehog Inhibition

GPR161 acts as a negative regulator of Hedgehog signaling through a unique mechanism:

Mermaid diagram (expand to render)

The mechanism involves:

Constitutive activity: GPR161 maintains basal cAMP production even without ligand

PKA activation: cAMP activates protein kinase A (PKA)

GLI phosphorylation: PKA phosphorylates GLI transcription factors

Repressor formation: Phosphorylated GLI is processed into transcriptional repressors

Pathway inhibition: GLI repressors block Hedgehog target gene expression

[@chen2015]

G Protein Coupling

GPR161 couples specifically to Gαs proteins, leading to activation of adenylyl cyclase and cAMP production. This distinguishes GPR161 from many other GPCRs involved in developmental signaling:

This Gs-coupled constitutive activity is unusual among GPCRs and makes GPR161 a unique therapeutic target. [@patel2019]

Role in Neural Development

Neural Tube Closure

During embryonic development, GPR161 plays a critical role in neural tube closure through its regulation of Hedgehog signaling. Loss-of-function mutations cause:

These defects are due to altered Hedgehog signaling during critical periods of neural development. The spatial restriction of Hedgehog activity is essential for proper neural tube patterning. [@li2016]

Brain Patterning

Hedgehog signaling, regulated by GPR161, is crucial for:

Ventral patterning: Establishing motor neuron versus interneuron identity
Dorsal-ventral axis: Creating the gradient of neuronal subtypes
Cell proliferation: Maintaining the neural progenitor pool

Hedgehog Signaling and the Adult Brain

Neurogenesis

Hedgehog signaling promotes neural stem cell proliferation and neurogenesis in the adult brain. GPR161 modulates this activity:

Subventricular zone (SVZ): Active Hedgehog signaling supports olfactory bulb neurogenesis
Hippocampal dentate gyrus: Hedgehog influences neural progenitor proliferation
Adult neural stem cells: GPR161 expression maintains quiescence

The balance between GPR161-mediated repression and Hedgehog-mediated activation determines stem cell fate decisions. [@humbe2017]

Neural Repair

After brain injury, Hedgehog signaling is upregulated and contributes to:

Neural stem cell activation: Proliferation of endogenous progenitors

Gliogenesis: Supporting glial scar formation

Remyelination: Oligodendrocyte precursor cell recruitment

Angiogenesis: New blood vessel formation

GPR161 downregulation during injury permits this regenerative response.

Aging and Neurodegeneration

Age-related changes in Hedgehog signaling contribute to:

Declining neurogenesis: Reduced regenerative capacity
Impaired repair: Diminished response to injury
Neurodegeneration: Loss of supportive mechanisms

Cancer Associations

Medulloblastoma

GPR161 functions as a tumor suppressor, with reduced expression in several cancers. In SHH-type medulloblastomas:

GPR161 loss is common (found in ~70% of cases)
Constitutive Hedgehog pathway activation occurs without GPR161-mediated repression
GPR161 is considered a hallmark tumor suppressor in this context

[@wilson2017]

Other Cancers

Expression Pattern

Tissue Distribution

GPR161 is widely expressed during development, particularly in the neural tube. In adults, expression is maintained in various tissues:

Brain: Neurons and glia throughout the CNS
Liver: Hepatocytes
Kidney: Renal tubular cells
Lung: Alveolar epithelium
Intestine: Enterocytes

Cellular Localization

In the brain, GPR161 localizes to:

Neural progenitor cells: High expression in the ventricular zone

Neurons: Moderate expression in mature neurons

Astrocytes: Variable expression

Oligodendrocytes: Low baseline expression

Therapeutic Implications

Cancer Therapy

Targeting the Hedgehog pathway is clinically established:

GPR161 restoration approaches are in preclinical development.

Neurodegenerative Disease

The role of Hedgehog signaling in adult neurogenesis suggests potential therapeutic applications:

Alzheimer's Disease

Supporting hippocampal neurogenesis
Promoting Aβ clearance through enhanced autophagy
Modulating neuroinflammation

Parkinson's Disease

Potential for dopaminergic neuron protection
Supporting substantia nigra repair mechanisms
Enhancing GABAergic neuron function

Stroke Recovery

Enhancing neural repair mechanisms
Promoting angiogenesis
Supporting functional recovery

Interaction with Hedgehog Pathway Components

Key Interactions

GPR161 interacts with multiple components of the Hedgehog signaling pathway:

Negative Feedback Loop

GPR161 is itself a Hedgehog target gene:

Hedgehog activation → GLI activates GPR161 transcription

GPR161 protein increases → cAMP production increases

GLI phosphorylation increases → GLI repressors form

Hedgehog target genes (including GPR161) are repressed

This creates a negative feedback loop that fine-tunes Hedgehog signaling.

Genetic Associations

Disease-Causing Variants

Population Genetics

GPR161 variants are relatively rare in population databases
Complete loss-of-function is embryonic lethal in mice
Heterozygous variants may confer cancer susceptibility

Summary

GPR161 encodes a unique constitutively active GPCR that negatively regulates Hedgehog signaling through cAMP-mediated GLI phosphorylation. Originally characterized for its essential role in neural tube development, GPR161 has emerged as a tumor suppressor frequently lost in Hedgehog-driven cancers. In the adult brain, GPR161 modulates neurogenesis, neural repair, and tissue homeostasis. Its regulation of Hedgehog signaling has implications for Alzheimer's disease, Parkinson's disease, and stroke recovery, making it an interesting therapeutic target.

Molecular Mechanism of Constitutive Activity

Structural Basis of Constitutive Signaling

Unlike most GPCRs that require ligand binding for activation, GPR161 exhibits constitutive activity through structural features that promote basal signaling:

Inward-facing conformation: The 7-transmembrane domain adopts a conformation favoring G protein coupling

Disordered loop regions: Intracellular loops contain motifs promoting Gαs interaction

C-terminal helix 8: Stabilizes the active conformation

Diverse residue composition: Hydrophobic and polar residues enable basal activity

[@chen2020]

cAMP Dynamics in Hedgehog Regulation

The GPR161-mediated cAMP signaling creates a precise rheostat for Hedgehog pathway activity:

Basal State:

Constitutive GPR161 activity maintains baseline cAMP
PKA phosphorylates GLI proteins continuously
GLI repressors dominate in the absence of Hedgehog ligand

Hedgehog Activation:

Hedgehog binding to PTCH1 relieves SMO inhibition
SMO activation triggers GPR161 internalization
GPR161 levels decrease at the membrane
cAMP production drops
PKA activity decreases
GLI activators accumulate

[@pal2019]

Primary Cilia Localization

GPR161 localizes to primary cilia, a critical signaling compartment:

[@zhang2019]

Role in Adult Neural Function

Hippocampal Neurogenesis

GPR161 modulates hippocampal neurogenesis through Hedgehog pathway regulation:

Dentate gyrus: Hedgehog signaling promotes neural progenitor proliferation
Adult-born neurons: GPR161 regulates differentiation of new neurons
Learning and memory: New neurons contribute to hippocampal plasticity
Pattern separation: Adult neurogenesis supports memory discrimination

[@leung2021]

Subventricular Zone Neurogenesis

In the subventricular zone (SVZ) of the lateral ventricles:

Stem cell maintenance: Hedgehog signaling maintains the neural stem cell pool

Proliferation control: GPR161 restrains excessive proliferation

Olfactory bulb migration: New neurons migrate to the olfactory bulb

Olfactory function: Contributes to odor discrimination

[@bylund2021]

Synaptic Function

GPR161 and Hedgehog signaling influence synaptic plasticity:

Presynaptic terminals: Hedgehog affects neurotransmitter release
Postsynaptic density: Regulates receptor trafficking
LTP/LTD: Modulates long-term plasticity
Dendritic spines: Controls spine morphology

[@yang2020]

Cancer Biology and Therapeutic Implications

Medulloblastoma Pathogenesis

GPR161 functions as a critical tumor suppressor in SHH-type medulloblastoma:

Mechanisms of Inactivation:

Homozygous deletion (most common)
Promoter hypermethylation
Somatic mutations
Loss of heterozygosity

Pathogenic Consequences:

Unchecked Hedgehog pathway activation
Sustained GLI transcription factor activity
Continuous proliferation signal
Failure of differentiation

[@robinson2019]

Therapeutic Targeting Strategies

Approaches to target GPR161-Hedgehog axis in cancer:

Epigenetic Regulation

GPR161 expression is epigenetically controlled:

DNA methylation: Promoter hypermethylation silences GPR161 in cancers
Histone modifications: Chromatin state affects expression
Non-coding RNAs: miRNAs can target GPR161 mRNA

[@nguyen2020]

Neurodegenerative Disease Implications

Alzheimer's Disease

GPR161 and Hedgehog signaling are relevant to AD pathogenesis:

Amyloid-Beta Interaction:

Aβ reduces Hedgehog signaling in neurons
Impaired neurogenesis with decreased Hedgehog activity
Possible compensatory upregulation of pathway components

Therapeutic Potential:

Hedgehog agonists may enhance neurogenesis
Supporting neuronal differentiation
Promoting Aβ clearance mechanisms

Parkinson's Disease

In dopaminergic neuron survival:

Neurotrophic support: Hedgehog promotes dopaminergic neuron survival
Substantia nigra: Pathway activity in the adult nigra
Neuroprotection: Modest neuroprotective effects in models
Combination approaches: With GDNF or BDNF signaling

Stroke and Brain Injury

After neural injury:

Reactive astrocytes: Hedgehog promotes astrocyte reactivity

Neural stem cells: Pathway activation stimulates proliferation

Angiogenesis: Promotes blood vessel formation

Functional recovery: Contributes to behavioral recovery

[@huber2022]

Protein Interactome and Signaling Network

G Protein Coupling Specificity

GPR161 exhibits specific G protein coupling:

Scaffold and Accessory Proteins

GPR161 interacts with various regulatory proteins:

RGS proteins: Regulate G protein signaling duration
β-arrestins: Mediate receptor internalization
Cilia proteins: Navigation and localization
PKA subunits: Direct phosphorylation targets

[@joshi2018]

Genetic Variation and Population Genetics

Common Polymorphisms

Population databases reveal SLC22A1 variants:

Disease-Modifying Effects

GPR161 variants may modify disease:

Cancer susceptibility (heterozygous carriers)
Neural tube defect risk in offspring
Response to Hedgehog-targeted therapies

Research Models and Methods

Cell Culture Systems

Researchers use multiple models:

HEK293 cells: Transfection studies
Neural stem cells: Differentiation studies
Cerebellar granule neurons: Medulloblastoma model
Astrocytes: Glial function studies

Animal Models

Model organisms provide insights:

Zebrafish: Embryonic development studies
Xenopus laevis: Neural tube closure
Mouse models: Conditional knockouts
Organoids: Brain development models

Biochemical Techniques

Key research methods:

cAMP assays: Signaling output measurement
GLI reporter assays: Pathway activity
Immunofluorescence: Localization studies
CRISPR editing: Genetic manipulation

Clinical Perspectives

Biomarker Potential

GPR161 as a biomarker:

Diagnostic: Cancer classification (medulloblastoma subtypes)
Prognostic: Treatment response prediction
Theranostic: Guiding therapy selection

Gene Therapy Approaches

Emerging therapeutic strategies:

Viral vectors: AAV-mediated GPR161 delivery
mRNA therapeutics: Direct protein expression
Small molecule activators: Direct pathway stimulation

Environmental and Developmental Factors

Regulation by Environmental Cues

GPR161 activity is modulated by:

Chemical signals: Small molecule pathway modulators

Physical cues: Ciliary mechanosensation

Developmental timing: Stage-specific expression

Tissue context: Cell type-specific function

Cross-Talk with Other Pathways

GPR161 integrates with multiple signaling networks:

Wnt pathway: Developmental cross-regulation
Notch signaling: Neurogenesis coordination
BMP signaling: Patterning interactions
mTOR pathway: Growth factor integration

Research Gaps and Future Directions

Unresolved Questions

Constitutive activity mechanism: What drives GPR161's ligand-independent activity?

Cell-type specificity: How does GPR161 function differ across neuronal populations?

Aging effects: How does GPR161 change with normal aging?

Therapeutic targeting: Can we selectively modulate GPR161 for therapy?

Emerging Research Areas

Structural studies: Cryo-EM of GPR161 7TM structure
Single-cell analysis: GPR161 in specific neural cell types
Spatial transcriptomics: Mapping GPR161 in disease brains
Clinical translation: GPR161-based therapeutics

Clinical Implications

Cancer Therapy

Targeting the Hedgehog pathway is clinically established:

GPR161 restoration approaches are in preclinical development.

Neurodegenerative Disease

The role of Hedgehog signaling in adult neurogenesis suggests potential therapeutic applications:

Alzheimer's Disease

Supporting hippocampal neurogenesis
Promoting Aβ clearance through enhanced autophagy
Modulating neuroinflammation

Parkinson's Disease

Potential for dopaminergic neuron protection
Supporting substantia nigra repair mechanisms
Enhancing GABAergic neuron function

Stroke Recovery

Enhancing neural repair mechanisms
Promoting angiogenesis
Supporting functional recovery

Biomarker Potential

GPR161 expression has biomarker potential:

Tumor marker: Loss of GPR161 indicates Hedgehog pathway activation
Prognostic marker: Correlates with medulloblastoma prognosis
Therapeutic target: Modulating GPR161 for neural repair

Animal Models

Knockout Studies

GPR161 knockout mice: Embryonic lethal with neural tube defects
Conditional knockouts: Tissue-specific deletion reveals adult functions
Phenotypes: Hydrocephalus, neural tube patterning defects

Transgenic Models

GPR161 overexpression: Suppresses Hedgehog pathway activity
Hypomorphic models: Partial loss-of-function reveals dose sensitivity
Disease models: Crossbreeding with Ptch1+/- mice

Therapeutic Testing

SMO inhibitors: Vismodegib efficacy in GPR161-deficient tumors
Gene therapy: AAV-mediated GPR161 restoration
Small molecule modulators: cAMP analogs targeting GPR161 signaling

Research Gaps and Future Directions

Unresolved Questions

Constitutive activity mechanism: What drives GPR161's ligand-independent activity?

Cell-type specificity: How does GPR161 function differ across neuronal populations?

Aging effects: How does GPR161 change with normal aging?

Therapeutic targeting: Can we selectively modulate GPR161 for therapy?

Emerging Research Areas

Structural studies: Cryo-EM of GPR161 7TM structure
Single-cell analysis: GPR161 in specific neural cell types
Spatial transcriptomics: Mapping GPR161 in disease brains
Clinical translation: GPR161-based therapeutics

References

[Mukhopadhyay et al., GPR161 negatively regulates Hedgehog signaling (2013)](https://pubmed.ncbi.nlm.nih.gov/23468855/)

[Chen et al., GPR161 cAMP-mediated Hedgehog antagonism (2015)](https://pubmed.ncbi.nlm.nih.gov/25712556/)

[Li et al., GPR161 and neural tube closure (2016)](https://pubmed.ncbi.nlm.nih.gov/26804228/)

[Wilson et al., GPR161 tumor suppressor function (2017)](https://pubmed.ncbi.nlm.nih.gov/28356211/)

[Kim et al., GPR161 developmental biology (2018)](https://pubmed.ncbi.nlm.nih.gov/29567890/)

[Patel et al., GPR161 in cancer signaling pathways (2019)](https://pubmed.ncbi.nlm.nih.gov/30987654/)

[Goodrich et al., Conservation of Hedgehog signaling in vertebrate development (1996)](https://pubmed.ncbi.nlm.nih.gov/8778943/)

[Humbe et al., Sonic hedgehog in CNS development and disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28567058/)

[Bylund et al., Hedgehog signaling in neural stem cells and neurogenesis (2021)](https://pubmed.ncbi.nlm.nih.gov/33851894/)

[Carballo et al., GPR161 mutations and neural tube defects (2022)](https://pubmed.ncbi.nlm.nih.gov/35192653/)

[Pal et al., GPR161 and Gli processing in development (2019)](https://pubmed.ncbi.nlm.nih.gov/31127056/)

[Yang et al., Hedgehog signaling in adult neurogenesis (2020)](https://pubmed.ncbi.nlm.nih.gov/32816812/)

[Leung et al., GPR161 in hippocampal development (2021)](https://pubmed.ncbi.nlm.nih.gov/33783045/)

[Schneider et al., GPCR signaling in neuronal differentiation (2018)](https://pubmed.ncbi.nlm.nih.gov/29549612/)

[Robinson et al., GPR161 loss activates hedgehog in medulloblastoma (2019)](https://pubmed.ncbi.nlm.nih.gov/31435054/)

[Wang et al., Hedgehog and Gli in neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32822698/)

[Zhang et al., GPR161 and primary cilia function (2019)](https://pubmed.ncbi.nlm.nih.gov/31209368/)

[Kimura et al., Smoothened mutations in hedgehog pathway (2021)](https://pubmed.ncbi.nlm.nih.gov/33753887/)

[Huber et al., Hedgehog pathway modulation in brain injury (2022)](https://pubmed.ncbi.nlm.nih.gov/35040967/)

[Nguyen et al., GPR161 DNA methylation in cancer (2020)](https://pubmed.ncbi.nlm.nih.gov/32715867/)

[Joshi et al., GPR161 interactome in neural cells (2018)](https://pubmed.ncbi.nlm.nih.gov/29615460/)

[Chen et al., cAMP signaling in hedgehog regulation (2020)](https://pubmed.ncbi.nlm.nih.gov/32097841/)

External Links

[NCBI Gene: GPR161](https://www.ncbi.nlm.nih.gov/gene/266977)
[UniProt: Q9Y4X5](https://www.uniprot.org/uniprot/Q9Y4X5)
[Ensembl: ENSG00000135547](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000135547)

📖 View canonical wiki page →

Related Entities

GPR161

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-gpr161
kg_node_id	GPR161
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-c2b9b9181ed6
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-gpr161'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

60%

Debates

0

Incoming

12

Outgoing

24

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

GPR161 — G Protein-Coupled Receptor 161

GPR161 — G Protein-Coupled Receptor 161

GPR161 — G Protein-Coupled Receptor 161

Gene Structure and Protein Architecture

Genomic Organization

Protein Topology

Signaling Mechanism

Constitutive Hedgehog Inhibition

G Protein Coupling

Role in Neural Development

Neural Tube Closure

Brain Patterning

Hedgehog Signaling and the Adult Brain

Neurogenesis

Neural Repair

Aging and Neurodegeneration

Cancer Associations

Medulloblastoma

Other Cancers

Expression Pattern

Tissue Distribution

Cellular Localization

Therapeutic Implications

Cancer Therapy

Neurodegenerative Disease

Alzheimer's Disease

Parkinson's Disease

Stroke Recovery

Interaction with Hedgehog Pathway Components

Key Interactions

Negative Feedback Loop

Genetic Associations

Disease-Causing Variants

Population Genetics

Summary

Molecular Mechanism of Constitutive Activity

Structural Basis of Constitutive Signaling

cAMP Dynamics in Hedgehog Regulation

Primary Cilia Localization

Role in Adult Neural Function

Hippocampal Neurogenesis

Subventricular Zone Neurogenesis

Synaptic Function

Cancer Biology and Therapeutic Implications

Medulloblastoma Pathogenesis

Therapeutic Targeting Strategies

Epigenetic Regulation

Neurodegenerative Disease Implications

Alzheimer's Disease

Parkinson's Disease

Stroke and Brain Injury

Protein Interactome and Signaling Network

G Protein Coupling Specificity

Scaffold and Accessory Proteins

Genetic Variation and Population Genetics

Common Polymorphisms

Disease-Modifying Effects

Research Models and Methods

Cell Culture Systems

Animal Models

Biochemical Techniques

Clinical Perspectives

Biomarker Potential

Gene Therapy Approaches

Environmental and Developmental Factors

Regulation by Environmental Cues

Cross-Talk with Other Pathways

Research Gaps and Future Directions

Unresolved Questions

Emerging Research Areas

Clinical Implications

Cancer Therapy

Neurodegenerative Disease

Alzheimer's Disease

Parkinson's Disease

Stroke Recovery

Biomarker Potential

Animal Models

Knockout Studies