GPR12

Official Full Name

G protein-coupled receptor 12

Organism

Homo sapiens

Gene ID

2835

Background

Predicted to enable G protein-coupled receptor activity. Predicted to be involved in adenylate cyclase-activating G protein-coupled receptor signaling pathway and regulation of metabolic process. Predicted to act upstream of or within G protein-coupled receptor signaling pathway and intracellular calcium ion homeostasis. Predicted to be located in membrane. Predicted to be active in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

GPCR12; GPCR21; PPP1R84

Cat.No.	Product Name	Price
CSC-DC006518	Panoply™ Human GPR12 Knockdown Stable Cell Line	Inquiry
CSC-SC006518	Panoply™ Human GPR12 Over-expressing Stable Cell Line	Inquiry

Cat.No.	Product Name	Price
LV13925L	human GPR12 (NM_005288) lentivirus particles	Inquiry

Cat.No.	Product Name	Price
SHH096077	shRNA set against Rat Gpcr12(NM_030831.1)	Inquiry
SHH096095	shRNA set against Rat Gpcr12(NM_001037295.1)	Inquiry
SHH097481	shRNA set against Mouse Gpr12(NM_001010941.2)	Inquiry
SHH097517	shRNA set against Mouse Gpr12(NM_008151.3)	Inquiry
SHH306158	shRNA set against Human GPR12 (NM_005288.3)	Inquiry
SHH306162	shRNA set against Mouse GPR12 (NM_008151.3)	Inquiry
SHH306166	shRNA set against Rat GPR12 (NM_030831.1)	Inquiry

Cat.No.	Product Name	Price
OE-PNDC000691	Human GPR12 Nanodisc	Inquiry

Cat.No.	Product Name	Price
CDCL113831	Mouse Gpr12 ORF clone (NM_001010941.2)	Inquiry
CDFR004509	Rat Gpr12 cDNA Clone(NM_001037295.1)	Inquiry
CDFR012363	Rat Gpr12 cDNA Clone(NM_030831.1)	Inquiry
MiUTR1M-05282	GPR12 miRNA 3'UTR clone	Inquiry
MiUTR1M-05283	GPR12 miRNA 3'UTR clone	Inquiry
MiUTR1R-02208	GPR12 miRNA 3'UTR clone	Inquiry
MiUTR1R-02209	GPR12 miRNA 3'UTR clone	Inquiry
CDCB185904	Rabbit GPR12 ORF clone (XM_008259883.1)	Inquiry
CDCR244974	Mouse Gpr12 ORF Clone(NM_008151.3)	Inquiry
CDCR371549	Rat Gpr12 ORF Clone(NM_001037295.1)	Inquiry
CDCR379410	Rat Gpr12 ORF Clone(NM_030831.1)	Inquiry

Detailed Information

G protein-coupled receptor 12 (GPR12) belongs to the rhodopsin families of G protein-coupled receptors (GPCRs), which are crucial therapeutic targets. GPR12 was first cloned from a mouse cDNA library in 1993 and was originally named GPCR21. This was followed by cloning of human GPR12, along with the two related orphan receptors GPR3 and GPR6, from a human genomic DNA library. In the brain, GPR12 is located in the medial habenular nucleus, and to a lesser extent in cerebral cortex, hippocampus, striatum, and olfactory bulb. Peripherally GPR12 is found in the testis and oocytes. GPR12 is involved in several physiological processes. For instance, GPR12 plays an important role in meiotic arrest in rat oocytes. Furthermore, GPR12 participates in the process of neurite outgrowth and could contribute to brain development.

GPR12 and neurite outgrowth and neuronal development

The lab of Ignatov et al. showed that the lysophospholipid SPC is a high-affinity ligand for GPR12. In vitro cell culture suggested that embryonic cerebral cortical neurons had increased synaptic contacts following SPC treatment, and HT22 hippocampal cells exhibited increased cell proliferation and clustering in response to SPC. These results led the lab to conclude that by interacting with GPR12, SPC can positively influence the proliferation of neuronal precursor cells and the differentiation and maturation process of post-mitotic neurons. As with GPR3 and GPR6, Tanaka et al. revealed that GPR12 overexpression also increased neurite outgrowth. In fact, GPR12-mediated outgrowth was the most prominent of the three receptors. In experiments in which GPR3 was knocked down, GPR12 also rescued neurite outgrowth. However, similar to GPR6, GPR12 exhibits low expression in rat cerebellar granule neurons. In 2012, Lu et al. showed that GPR12 induces neurite outgrowth in PC12 cells. The authors demonstrated that GPR12 overexpression instigated the differentiation of PC12 cells into neuron-like cells with the increased size of the cell and neurite generation. The researchers proposed that a possible mechanism for this phenotype is the activation of ERK1/2 signaling and a substantial increase in the expression of multiple genes related to neurite outgrowth.

GPR12 and obesity and metabolic disorders

Bjursell et al. investigated the importance of GPR12 in metabolism. They found that food intake was not significantly affected in GPR12 knockout mice compared to wild-type mice. However, the GPR12 knockout mice exhibited increased body weight and body fat mass, decreased respiratory exchange ratio, dyslipidemia, and hepatic steatosis. The authors concluded that GPR12 plays an important role in energy balance, which is supported by the fact that GPR12 knockout mice developed obesity and decreased energy expenditure.

A novel molecular target for Cannabidiol

In spite of being orphans, GPR12 share about 35% amino acid sequence identity in the transmembrane regions with the CB1 and CB2 cannabinoid receptors. Thus, it is considered a “cannabinoid receptor-like orphan GPCR”. The research has shown that cannabidiol (CBD), a major non-psychoactive phytocannabinoid, played as an inverse agonist to inhibit cAMP accumulation stimulated by the constitutively active GPR12. Therefore, GPR12 is a novel molecular target for CBD. The structure-activity relationship studies of CBD indicate that both the free hydroxyl and the pentyl side chain are critical for the effects of CBD on GPR12. In addition, studies using cholera toxin, which blocks G_s protein and pertussis toxin, which blocks G_i protein, revealed that G_s, but not G_i is involved in the inverse agonism of CBD on GPR12. CBD is a promising novel therapeutic agent for cancer, and GPR12 has been shown to alter the viscoelasticity of metastatic cancer cells. Since these studies have shown that CBD is an inverse agonist for GPR12, this provides a novel mechanism of action for CBD, and an initial chemical scaffold upon which highly potent and efficacious agents acting on GPR12 may be developed with the ultimate goal of blocking cancer metastasis.

References:

Brown K J, et al. Cannabidiol, a novel inverse agonist for GPR12. Biochemical and Biophysical Research Communications, 2017:S0006291X1731759X.
Laun A S, et al. GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol. Acta Pharmacologica Sinica, 2018.
Lu X, et al. Involvement of GPR12 in the induction of neurite outgrowth in PC12 cells. Brain Research Bulletin, 2012, 87(1):0-36.
Lu X, et al. Involvement of GPR12 in the regulation of cell proliferation and survival. Molecular and Cellular Biochemistry, 2012, 366(1-2):101-110.
Morales P, et al. Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12. Drug Metabolism Reviews, 2018:1-20.

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