GPR3

Last updated
GPR3
Identifiers
Aliases GPR3 , ACCA, G protein-coupled receptor 3
External IDs OMIM: 600241 MGI: 101908 HomoloGene: 31303 GeneCards: GPR3
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005281

NM_008154

RefSeq (protein)

NP_005272

NP_032180

Location (UCSC) Chr 1: 27.39 – 27.4 Mb Chr 4: 132.94 – 132.94 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

G-protein coupled receptor 3 is a protein that in humans is encoded by the GPR3 gene. [5] [6] The protein encoded by this gene is a member of the G protein-coupled receptor family of transmembrane receptors and is involved in signal transduction.

Contents

GPR3 mRNA is broadly expressed in neurons in various brain regions, including the cortex, thalamus, hypothalamus, amygdala, hippocampus, pituitary, and cerebellum. [7] [8] GPR3 mRNA is also expressed in the eye, lung, kidney, liver, testes, and ovary, among other tissues. [9]

Individuals afflicted by Alzheimer's disease have in many cases, overexpression of the GPR3 protein in their neurons. [10]

Function

GPR3 activates adenylate cyclase in the absence of ligand. [11] GPR3 was first described as a constitutive activator of adenylate cyclase. This constitutive activity could be due to stimulation by a ubiquitous ligand that may be free, membrane-bound, or membrane-derived. Alternatively, they propose that this could also be due to basal Gs coupling. Various groups have since supported this initial finding of GPR3 constitutive activation and have proceeded to show similar Gs activity in GPR6 and GPR12.

GPR3 is expressed in mammalian oocytes where it maintains meiotic arrest and is thought to be a communication link between oocytes and the surrounding somatic tissue. [12] It has been proposed that sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) are GPR3 ligands, [13] [8] however this result was not confirmed in a β-arrestin recruitment assay. [14]

Mice lacking GPR3 were found to develop late-onset obesity owing to decreased UCP-1 expression in brown adipose tissue and reduced thermogenic capacity. [15]

Brown adipose tissue Activation

Brown adipose tissue (BAT), in contrast to bona fide white fat, can dissipate significant amounts of chemical energy through uncoupled respiration and heat production (thermogenesis). Metabolic substrates are consumed to fuel mitochondrial futile cycles and uncoupling protein 1 (UCP1)-dependent respiration to ultimately convert chemical energy to heat. Gs-signaling stimulates the recruitment of thermogenically competent beige adipocytes in the subcutaneous adipose depots.

Exposure to environmental cold stimulates thermogenic catabolism of lipids and carbohydrates in brown adipose tissue (BAT).

BAT activation is predominantly ascribed to the Gs-coupled family, which signals through increased cyclic AMP (cAMP). This class is exemplified by the β-adrenergic receptors (ADRB1, ADRB2, and ADRB3), which represent the canonical means of sympathetic, ligand-mediated thermogenic control.

However, in the case of Gpr3, cold exposure increases the expression of this constitutively active receptor, which possesses innate signaling capacity and, thus, can modulate cAMP levels and thermogenic output without a ligand. [16]

Gpr3 expression must be kept at extremely low basal levels until there is a thermogenic demand. Mimicking the cold induction of Gpr3 is then sufficient to drive and maintain elevated BAT activity even under conditions of little or no sympathetic tone.

To prove this, OS Johansen and colleagues developed a conditional gain-of-function model (Gpr3 TTG) for robust and sustained genetic manipulation of Gpr3 in vitro and in vivo.

Gpr3 TTG mice were crossed with mice to facilitate overexpression of Gpr3 in isolated primary brown and subcutaneous white adipocytes. Gpr3 overexpression significantly increased the expression of thermogenic genes, fatty acid uptake, and basal and leak mitochondrial respiration.

Gpr3 overexpression in their primary adipocyte model suppressed expression of the β-adrenergic receptors, further supporting a counter-regulatory interaction between GPR3 and other Gs-coupled receptors.

BAT-specific overexpression of Gpr3 (C-3BO) mice were completely protected from developing diet-induced obesity despite maintaining comparable levels of food intake, C-3BO mice maintained elevated whole-body energy expenditure as well as darker brown BAT depots and higher thermogenic gene expression. [16]

Reproductive system

In mammalian oocytes, the process of meiotic arrest and meiotic maturation is controlled by in large part by cAMP concentrations in the cell.  When cAMP levels in the cell decrease the process of miosis resumes and this precedes germinal vesicle breakdown. [17] It is proposed That GPR3 is implicated in cAMP signaling in oocytes since it is consistent with the observation that their mRNA expression is reduced when cAMP is chronically increased in oocytes. The constitutive activity of these receptors is sufficient to prevent maturation in mouse oocytes, it is shown that their activity is also sufficient for maintaining the meiotic arrest in the follicle. [8]

Brain cells

GPR3 mRNA is broadly expressed in neurons in various brain regions, including the cortex, thalamus, hypothalamus, amygdala, hippocampus, pituitary, and cerebellum. Notably, the GPR3 protein is overexpressed in neurons in post-mortem brain tissue sections from individuals afflicted by Alzheimer's disease. [7] In a study on mice with Alzheimer's disease, it was shown that the disruption of the expression of GPR3 has affected the overgrowth of amyloid plaque on neurons, helping symptoms of Alzheimer's disease. [18]

Ligands

GPR3 is largely known as an orphan G protein-coupled receptor. Even though it does not have any endogenous ligands there is research being conducted to find non-endogenous agonists for the receptor. [19] [13] [20]

Agonists

Sphingosine 1-phosphate

The molecule Sphingosine 1-phosphate (S1P) is a signaling lipid that exists in the extracellular plasma, its synthesis is catalysed by sphingosine kinases (SphKs). [19] The molecule is reported to have high affinity to the GPR3 receptor. The proposed ligand activates the Gs signaling pathway in oocytes. [13]

Diphenyleneiodonium chloride

Diphenyleneiodonium chloride (DPI) is an inhibitor of NADPH oxidase and a potent, irreversible, and time and temperature-dependent iNOS/eNOS inhibitor. Diphenyleneiodonium chloride (DPI) also functions as a TRPA1 activator and selectively inhibits intracellular reactive oxygen species (ROS). Diphenyleneiodonium chloride (DPI) was identified as a novel agonist of GPR3 with weak or no cross-reactivity with other GPCRs. DPI was further characterized to activate several GPR3-mediated signal transduction pathways, including Ca(2+) mobilization, cAMP accumulation, membrane recruitment of β-arrestin2, and receptor desensitization. [20]

Inverse agonists

Cannabidiol

Cannabidiol (CBD) is a Phyto-cannabinoid found in the cannabis plant. This compound is connected to improving anxiety, cognition, and pain. Although it is orphan, GPR3 is phylogenetically most closely related to the cannabinoid receptors. Using β-arrestin2 recruitment and cAMP accumulation assays, it was recently found that cannabidiol is an inverse agonist for GPR3. The affects that the inverse agonist has are still unknown. [21]

Evolution

Paralogues

Source: [22]

Related Research Articles

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G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. They are coupled with G proteins. They pass through the cell membrane seven times in the form of six loops of amino acid residues, which is why they are sometimes referred to as seven-transmembrane receptors. Ligands can bind either to the extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists, although a spontaneous auto-activation of an empty receptor has also been observed.

<span class="mw-page-title-main">Oogenesis</span> Egg cell production process

Oogenesis, ovogenesis, or oögenesis is the differentiation of the ovum into a cell competent to further develop when fertilized. It is developed from the primary oocyte by maturation. Oogenesis is initiated in the embryonic stage.

A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor that is transduced to the cell interior through second messengers which amplify the signal and transfer it to effector molecules, causing the cell to respond to the initial stimulus. Most biochemical cascades are series of events, in which one event triggers the next, in a linear fashion. At each step of the signaling cascade, various controlling factors are involved to regulate cellular actions, in order to respond effectively to cues about their changing internal and external environments.

<span class="mw-page-title-main">Liver X receptor</span> Nuclear receptor

The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.

<span class="mw-page-title-main">ACTH receptor</span> Mammalian protein found in Homo sapiens

The adrenocorticotropic hormone receptor or ACTH receptor also known as the melanocortin receptor 2 or MC2 receptor is a type of melanocortin receptor (type 2) which is specific for ACTH. A G protein–coupled receptor located on the external cell plasma membrane, it is coupled to Gαs and upregulates levels of cAMP by activating adenylyl cyclase. The ACTH receptor plays a role in immune function and glucose metabolism.

<span class="mw-page-title-main">Gustducin</span> G protein

Gustducin is a G protein associated with taste and the gustatory system, found in some taste receptor cells. Research on the discovery and isolation of gustducin is recent. It is known to play a large role in the transduction of bitter, sweet and umami stimuli. Its pathways are many and diverse.

G<sub>s</sub> alpha subunit Mammalian protein found in Homo sapiens

The Gs alpha subunit is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding member of one of the four families of heterotrimeric G proteins, defined by the alpha subunits they contain: the Gαs family, Gαi/Gαo family, Gαq family, and Gα12/Gα13 family. The Gs-family has only two members: the other member is Golf, named for its predominant expression in the olfactory system. In humans, Gsα is encoded by the GNAS complex locus, while Golfα is encoded by the GNAL gene.

<span class="mw-page-title-main">S1PR1</span> Protein and coding gene in humans

Sphingosine-1-phosphate receptor 1, also known as endothelial differentiation gene 1 (EDG1) is a protein that in humans is encoded by the S1PR1 gene. S1PR1 is a G-protein-coupled receptor which binds the bioactive signaling molecule sphingosine 1-phosphate (S1P). S1PR1 belongs to a sphingosine-1-phosphate receptor subfamily comprising five members (S1PR1-5). S1PR1 was originally identified as an abundant transcript in endothelial cells and it has an important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation and vascular maturation. In addition, S1PR1 signaling is important in the regulation of lymphocyte maturation, migration and trafficking.

<span class="mw-page-title-main">Estrogen-related receptor alpha</span> Protein-coding gene in the species Homo sapiens

Estrogen-related receptor alpha (ERRα), also known as NR3B1, is a nuclear receptor that in humans is encoded by the ESRRA gene. ERRα was originally cloned by DNA sequence homology to the estrogen receptor alpha, but subsequent ligand binding and reporter-gene transfection experiments demonstrated that estrogens did not regulate ERRα. Currently, ERRα is considered an orphan nuclear receptor.

<span class="mw-page-title-main">S1PR3</span> Protein and coding gene in humans

Sphingosine-1-phosphate receptor 3 also known as S1PR3 is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P). Hence this receptor is also known as S1P3.

<span class="mw-page-title-main">GPR6</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 6, also known as GPR6, is a protein which in humans is encoded by the GPR6 gene.

<span class="mw-page-title-main">GPR12</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 12 is a protein that in humans is encoded by the GPR12 gene.

<span class="mw-page-title-main">GPR65</span> Protein-coding gene in the species Homo sapiens

Psychosine receptor is a G protein-coupled receptor (GPCR) protein that in humans is encoded by the GPR65 gene. GPR65 is also referred to as TDAG8.

<span class="mw-page-title-main">S1PR4</span> Protein-coding gene in the species Homo sapiens

Sphingosine-1-phosphate receptor 4 also known as S1PR4 is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P). Hence this receptor is also known as S1P4.

<span class="mw-page-title-main">S1PR2</span> Protein and coding gene in humans

Sphingosine-1-phosphate receptor 2, also known as S1PR2 or S1P2, is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P).

<span class="mw-page-title-main">Cannabinoid receptor 2</span> Mammalian protein found in Homo sapiens

The cannabinoid receptor 2(CB2), is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. It is closely related to the cannabinoid receptor 1 (CB1), which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol (THC), the active agent in cannabis, and other phytocannabinoids. The principal endogenous ligand for the CB2 receptor is 2-Arachidonoylglycerol (2-AG).

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<span class="mw-page-title-main">Prostacyclin receptor</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">GRK5</span> Protein-coding gene in the species Homo sapiens

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Membrane progesterone receptors (mPRs) are a group of cell surface receptors and membrane steroid receptors belonging to the progestin and adipoQ receptor (PAQR) family which bind the endogenous progestogen and neurosteroid progesterone, as well as the neurosteroid allopregnanolone. Unlike the progesterone receptor (PR), a nuclear receptor which mediates its effects via genomic mechanisms, mPRs are cell surface receptors which rapidly alter cell signaling via modulation of intracellular signaling cascades. The mPRs mediate important physiological functions in male and female reproductive tracts, liver, neuroendocrine tissues, and the immune system as well as in breast and ovarian cancer.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000181773 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000049649 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Marchese A, Docherty JM, Nguyen T, Heiber M, Cheng R, Heng HH, et al. (October 1994). "Cloning of human genes encoding novel G protein-coupled receptors". Genomics. 23 (3): 609–618. doi:10.1006/geno.1994.1549. PMID   7851889.
  6. "Entrez Gene: GPR3 G protein-coupled receptor 3".
  7. 1 2 Iismaa TP, Kiefer J, Liu ML, Baker E, Sutherland GR, Shine J (November 1994). "Isolation and chromosomal localization of a novel human G-protein-coupled receptor (GPR3) expressed predominantly in the central nervous system". Genomics. 24 (2): 391–394. doi:10.1006/geno.1994.1635. PMID   7698767.
  8. 1 2 3 Hinckley M, Vaccari S, Horner K, Chen R, Conti M (November 2005). "The G-protein-coupled receptors GPR3 and GPR12 are involved in cAMP signaling and maintenance of meiotic arrest in rodent oocytes". Developmental Biology. 287 (2): 249–261. doi: 10.1016/j.ydbio.2005.08.019 . PMID   16229830.
  9. Zhang B, Ding J, Li Y, Wang J, Zhao Y, Wang W, et al. (May 2012). "The porcine Gpr3 gene: molecular cloning, characterization and expression level in tissues and cumulus-oocyte complexes during in vitro maturation". Molecular Biology Reports. 39 (5): 5831–5839. doi:10.1007/s11033-011-1393-y. PMID   22207171. S2CID   18513825.
  10. Thathiah A, Spittaels K, Hoffmann M, Staes M, Cohen A, Horré K, et al. (February 2009). "The orphan G protein-coupled receptor 3 modulates amyloid-beta peptide generation in neurons". Science. 323 (5916): 946–951. Bibcode:2009Sci...323..946T. doi:10.1126/science.1160649. PMID   19213921. S2CID   30276731.
  11. Eggerickx D, Denef JF, Labbe O, Hayashi Y, Refetoff S, Vassart G, et al. (August 1995). "Molecular cloning of an orphan G-protein-coupled receptor that constitutively activates adenylate cyclase". The Biochemical Journal. 309 (Pt 3): 837–843. doi:10.1042/bj3090837. PMC   1135708 . PMID   7639700.
  12. Mehlmann LM, Saeki Y, Tanaka S, Brennan TJ, Evsikov AV, Pendola FL, et al. (December 2004). "The Gs-linked receptor GPR3 maintains meiotic arrest in mammalian oocytes". Science. 306 (5703): 1947–1950. Bibcode:2004Sci...306.1947M. doi:10.1126/science.1103974. PMID   15591206. S2CID   37342089.
  13. 1 2 3 Uhlenbrock K, Gassenhuber H, Kostenis E (November 2002). "Sphingosine 1-phosphate is a ligand of the human gpr3, gpr6 and gpr12 family of constitutively active G protein-coupled receptors". Cellular Signalling. 14 (11): 941–953. doi:10.1016/S0898-6568(02)00041-4. PMID   12220620.
  14. Yin H, Chu A, Li W, Wang B, Shelton F, Otero F, et al. (May 2009). "Lipid G protein-coupled receptor ligand identification using beta-arrestin PathHunter assay". The Journal of Biological Chemistry. 284 (18): 12328–12338. doi: 10.1074/jbc.M806516200 . PMC   2673301 . PMID   19286662.
  15. Godlewski G, Jourdan T, Szanda G, Tam J, Cinar R, Harvey-White J, et al. (October 2015). "Mice lacking GPR3 receptors display late-onset obese phenotype due to impaired thermogenic function in brown adipose tissue". Scientific Reports. 5: 14953. Bibcode:2015NatSR...514953G. doi:10.1038/srep14953. PMC   4601089 . PMID   26455425.
  16. 1 2 Sveidahl Johansen O, Ma T, Hansen JB, Markussen LK, Schreiber R, Reverte-Salisa L, et al. (June 2021). "Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis". Cell. 184 (13): 3502–3518.e33. doi:10.1016/j.cell.2021.04.037. PMC   8238500 . PMID   34048700.
  17. Schultz RM, Montgomery RR, Belanoff JR (June 1983). "Regulation of mouse oocyte meiotic maturation: implication of a decrease in oocyte cAMP and protein dephosphorylation in commitment to resume meiosis". Developmental Biology. 97 (2): 264–273. doi:10.1016/0012-1606(83)90085-4. PMID   6189752. S2CID   25357679.
  18. Huang Y, Skwarek-Maruszewska A, Horré K, Vandewyer E, Wolfs L, Snellinx A, et al. (October 2015). "Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer's disease mouse models". Science Translational Medicine. 7 (309): 309ra164. doi:10.1126/scitranslmed.aab3492. PMID   26468326. S2CID   35831952.
  19. 1 2 Spiegel S, Milstien S (May 2003). "Sphingosine-1-phosphate: an enigmatic signalling lipid". Nature Reviews. Molecular Cell Biology. 4 (5): 397–407. doi:10.1038/nrm1103. PMID   12728273. S2CID   22622224.
  20. 1 2 Ye C, Zhang Z, Wang Z, Hua Q, Zhang R, Xie X (June 2014). "Identification of a novel small-molecule agonist for human G protein-coupled receptor 3". The Journal of Pharmacology and Experimental Therapeutics. 349 (3): 437–443. doi:10.1124/jpet.114.213082. PMID   24633425. S2CID   27137928.
  21. Laun AS (2018). A study of GPR3, GPR6, of GPR12 as novel molecular targets for cannabidiol (M.S. thesis). University of Louisville. doi: 10.18297/etd/2945 .
  22. "Ensembl".

Further reading