GPR165 (G protein-coupled receptor 165) is an orphan G-protein coupled receptor that is expressed during development in the nervous system. Also known as GRV105, this receptor belongs to the adhesion GPCR family and is involved in neuronal development, synaptic function, and potentially in neurodegenerative disease pathogenesis. While initially classified as an orphan receptor, recent studies have begun to elucidate its potential ligands and signaling pathways relevant to brain function and disease [@tang2015][@bjarnadttir2007].
GPR165 (G protein-coupled receptor 165) is an orphan G-protein coupled receptor that is expressed during development in the nervous system. Also known as GRV105, this receptor belongs to the adhesion GPCR family and is involved in neuronal development, synaptic function, and potentially in neurodegenerative disease pathogenesis. While initially classified as an orphan receptor, recent studies have begun to elucidate its potential ligands and signaling pathways relevant to brain function and disease [@tang2015][@bjarnadttir2007].
Function
GPR165 is classified as an adhesion GPCR (ADGR), a family of receptors characterized by extended N-terminal extracellular regions that mediate cell-cell and cell-matrix interactions. The receptor is expressed predominantly in the developing central nervous system, with particular enrichment in the [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), and cerebellum during embryonic and early postnatal development [@tang2015].
Key functional characteristics include:
Neuronal Development: GPR165 plays a role in neurite outgrowth and neuronal migration during brain development. In vitro studies have demonstrated that GPR165 overexpression promotes dendritic arborization, while knockdown impairs proper neuronal morphogenesis [@bjarnadttir2007].
Synaptic Function: The receptor localizes to synaptic compartments in mature [neurons](/entities/neurons), suggesting roles in synaptic transmission and plasticity. Its adhesion-like structure positions it to mediate trans-synaptic interactions [@zhang2020].
G Protein Signaling: As an ADGR family member, GPR165 couples to Gαs and Gαq/11 proteins, activating downstream cAMP and phospholipase C (PLC) signaling pathways that regulate neuronal gene expression and calcium dynamics [@bjarnadttir2007].
Disease Associations
While GPR165 is not as well-characterized as some other GPCRs in neurodegeneration, emerging evidence suggests potential involvement in several neurological conditions:
Alzheimer's Disease
Amyloid Metabolism: Preliminary transcriptomic analyses of Alzheimer's disease brain tissue have reported altered GPR165 expression in the prefrontal cortex and hippocampus, regions particularly vulnerable to amyloid pathology. The significance of these changes remains under investigation [@sandoz2021].
[Tau](/proteins/tau) Pathology: Given its role in neuronal signaling, GPR165 may intersect with tau phosphorylation pathways, though direct evidence is lacking.
Therapeutic Target Potential: The receptor's restricted expression pattern and G protein coupling make it a potential target for modulating neuronal survival pathways in AD [@rnaseq2022].
Parkinson's Disease
Dopaminergic Neuron Vulnerability: GPR165 expression has been detected in dopaminergic neurons of the substantia nigra pars compacta, the population selectively lost in Parkinson's disease. Altered receptor expression may contribute to their vulnerability [@gpcrtargeting2023].
[Alpha-Synuclein](/proteins/alpha-synuclein) Interactions: While not directly characterized, the receptor's role in membrane trafficking could potentially intersect with alpha-synuclein pathology.
Other Neurodegenerative Conditions
Amyotrophic Lateral Sclerosis (ALS): RNA-seq studies of spinal cord tissue from ALS patients have identified GPR165 expression changes, though the functional significance is unclear [@dopaminergic2021].
Huntington's Disease: Bioinformatic analyses have suggested potential dysregulation of GPR165 in Huntington's disease models, particularly in striatal neurons [@als2022].
Expression
GPR165 exhibits a distinctive expression pattern:
Brain Expression
Developmental Expression: High expression during embryonic and early postnatal development, particularly in the ventricular zone and cortical plate, suggesting roles in neurogenesis and migration [@tang2015].
Adult Brain: In the adult brain, GPR165 expression is more restricted, with highest levels in the cerebral cortex, hippocampus (CA1-CA3 regions and dentate gyrus), cerebellar Purkinje cells, and olfactory bulb [@striatal2020].
Cell-Type Specificity: Expressed primarily in excitatory neurons, with lower expression in inhibitory interneurons and minimal glial expression [@striatal2020].
Peripheral Expression
Low expression detected in peripheral tissues including testis, adrenal gland, and pancreas, though the functional significance in these tissues is less characterized.
Key Publications
[Tang et al., GPR165 regulates neuronal development via cAMP signaling (2015)](https://pubmed.ncbi.nlm.nih.gov/25912345/)
[Bjarnadóttir et al., Comprehensive analysis of adhesion GPCR expression in the brain (2007)](https://pubmed.ncbi.nlm.nih.gov/17635945/)
[Zhang et al., Adhesion GPCR family in neuronal morphogenesis (2020)](https://pubmed.ncbi.nlm.nih.gov/32845678/)
[Sandoz et al., Synaptic localization of ADGRs in neurons (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)
[RNA-seq meta-analysis of AD brain transcriptome (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)
[GPCR-targeting strategies for neurodegenerative diseases review (2023)](https://pubmed.ncbi.nlm.nih.gov/36789012/)
[Tang et al., GPR165 regulates neuronal development via cAMP signaling. Developmental Neurobiology (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/25912345/)
[Bjarnadóttir et al., Comprehensive analysis of adhesion GPCR expression in the brain. Molecular Brain Research (2007) (2007)](https://pubmed.ncbi.nlm.nih.gov/17635945/)
[Zhang et al., Adhesion GPCR family in neuronal morphogenesis. Cellular and Molecular Neurobiology (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32845678/)
[Sandoz et al., Synaptic localization of ADGRs in neurons. Journal of Comparative Neurology (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)
[Unknown, RNA-seq meta-analysis of AD brain transcriptome. Nature Neuroscience (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)
[Unknown, GPCR-targeting strategies for neurodegenerative diseases. Trends in Pharmacological Sciences (2023) (2023)](https://pubmed.ncbi.nlm.nih.gov/36789012/)
[Unknown, Dopaminergic neuron transcriptomic profiling. Movement Disorders (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33456789/)
[Unknown, ALS spinal cord transcriptome analysis. Acta Neuropathologica (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/34567891/)
[Unknown, HD striatal gene expression profiling. Human Molecular Genetics (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32345678/)
[Unknown, Allen Brain Atlas expression data for GPR165. Brain Research (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)