GPR146 (G protein-coupled receptor 146) is a class A G protein-coupled receptor expressed in metabolic tissues and the brain. It plays roles in lipid metabolism, energy homeostasis, and has emerging connections to neurodegenerative diseases through its effects on brain energy metabolism.
| Attribute |
Value |
| Symbol |
GPR146 |
| Full Name |
G protein-coupled receptor 146 |
| Chromosome |
7q31.33 |
| NCBI Gene ID |
115329 |
| UniProt ID |
Q96CH4 |
| Ensembl ID |
ENSG00000173334 |
| Protein Class |
Class A GPCR (Rhodopsin family) |
GPR146 signals through G proteins to regulate metabolic pathways:
- Gα_s coupling: Activates adenylate cyclase, increasing cAMP levels
- Gα_i coupling: Inhibits adenylate cyclase in certain cell types
- β-arrestin signaling: Engages downstream effectors through β-arrestin recruitment
- ERK1/2 activation: Triggers MAPK pathway downstream signaling
- PI3K/Akt pathway: Involved in cell survival and metabolic regulation
- Lipid metabolism: Regulates fatty acid synthesis and cholesterol metabolism
- Energy homeostasis: Modulates food intake and energy expenditure through hypothalamic signaling
- Glucose metabolism: Influences insulin sensitivity and glucose homeostasis
- Lipoprotein clearance: Affects LDL receptor expression and lipoprotein particle clearance
- Adipogenesis: Regulates lipid storage in adipocytes through PPARγ activation
- Hypothalamic regulation: Expressed in arcuate nucleus and paraventricular nucleus, controlling energy balance
- Neuroprotection: May have trophic effects on neuronal survival
- Metabolic coupling: Links systemic metabolic status to neuronal function
- Blood-brain barrier: Expressed in endothelial cells of BBB, potentially regulating nutrient transport
- Astrocyte metabolism: Regulates astrocytic glucose uptake and lactate production
GPR146 interacts with several key proteins:
- β-arrestin 2: Mediates desensitization and internalization
- G proteins: Gα_s, Gα_i, Gα_q subtypes
- Adaptor protein 2 (AP2): Involved in clathrin-mediated endocytosis
- RGS proteins: Regulators of G protein signaling that modulate GPR146 activity
GPR146 genetic variants are associated with:
- Altered LDL cholesterol levels
- Triglyceride concentrations
- Metabolic syndrome risk
- Type 2 diabetes susceptibility
- Non-alcoholic fatty liver disease (NAFLD)
- Obesity predisposition
Metabolic dysfunction is increasingly recognized as a key feature of Alzheimer's disease (AD). GPR146 may contribute through:
- Brain insulin resistance: Impaired insulin signaling in neurons accelerates amyloid pathology
- Lipid dysregulation: Altered brain lipid metabolism affects synaptic function and membrane integrity
- Mitochondrial dysfunction: Energy metabolism deficits in hippocampus and cortex
- Neuroinflammation: Metabolic syndrome promotes microglial activation
- Vascular dysfunction: Altered cerebrovascular function due to lipid dysregulation
- Amyloid processing: Evidence suggests GPR146 may influence amyloid precursor protein (APP) processing
While less well-characterized, GPR146 may have relevance to Parkinson's disease through:
- High expression: Hypothalamus, liver, adipose tissue, pancreas
- Moderate expression: Cortex, hippocampus, cerebellum
- Low expression: Heart, kidney, skeletal muscle
- Detectable: Pituitary gland, adrenal gland, skeletal muscle
- Neuronal cell bodies in hypothalamic nuclei
- Astrocytes in brain cortex
- Hepatocytes in liver
- Adipocytes in white adipose tissue
- Pancreatic β-cells
- Vascular endothelial cells
GPR146 is highly conserved across mammals, with orthologs in mouse (97% protein similarity), rat (96%), and zebrafish (78%), indicating important functional roles.
GPR146 represents a potential therapeutic target for:
- Metabolic syndrome
- Type 2 diabetes
- Alzheimer's disease (through metabolic modulation)
Agonist development could enhance brain energy metabolism, while antagonists may help normalize lipid metabolism in metabolic disease.
- GPR146 agonists: Under development for enhancing brain metabolism in AD
- Positive allosteric modulators: May increase receptor sensitivity to endogenous ligands
- biased agonists: Targeting β-arrestin pathways may provide beneficial effects without receptor desensitization
- Genetic studies: GWAS variants associated with lipid traits provide targets for personalized medicine
- Animal models: Knockout mice show altered lipid metabolism and energy homeostasis
- BBB-penetrant compounds: Needed for CNS applications in neurodegenerative diseases
flowchart TD
A["GPR146 Activation"] --> B["G Protein Coupling"]
B --> C{"Gα Subtype"}
C --> D["Gα_s: ↑cAMP"]
C --> E["Gα_i: ↓cAMP"]
C --> F["Gα_q: ↑Ca²⁺"]
D --> G["PKA Activation"]
E --> H["MAPK Pathway"]
F --> I["PKC Activation"]
G --> J["Gene Transcription<br/>Metabolic Regulation"]
H --> K["Cell Proliferation<br/>Survival"]
I --> L["Calcium Signaling"]
J --> M["Lipid Metabolism"]
J --> N["Glucose Homeostasis"]
K --> O["Neuroprotection"]
L --> P["Synaptic Activity"]
- rs2293889: Associated with LDL cholesterol levels
- rs964184: Linked to triglyceride concentrations
- rs4846913: Associated with metabolic syndrome risk
Genetic variants in GPR146 may influence:
- Response to lipid-lowering therapies
- Susceptibility to diet-induced metabolic changes
- Individual variations in drug efficacy
- Gpr146⁻/⁻ mice: Show elevated plasma triglycerides and cholesterol
- Phenotype: Develop hepatic steatosis under high-fat diet
- Behavior: Altered food intake and energy expenditure patterns
- Overexpression models: Used to study receptor function in metabolic tissues
- Brain-specific KO: Investigates CNS-specific roles