DEFINITION
*GPR39 is a 51,589 Da G protein-coupled receptor
is emerging as an important regulator of gastrointestinal motility and secretion
Besides these effects, GPR39 have also physiological effects in regulating insulin secretion, gastric emptying,
neurotransmission and epithelial repair, neuronal plasticity and depression,
obesity and adipocyte metabolism, neurotrasmission,
skeletal myogenesis,
human esophageal cancer development.
GPR39 belong to the super family of G protein-coupled receptors (GPCRs).
GPR39 is a member of the ghrelin receptor family.
Ghrelin, is a peptide hormone derived from cleavage of the ghrelin/obestatin prepropeptide.
Obestatin
GPR39 is widely expressed in liver, stomach, pancreas, colon(anatomy), adipose tissues.
THE GENE
The human GPR39 gene is localized to chromosome 2q21-q22(location: Chromosome 2, NC_000002.11).
Official Symbol: GPR39
Other Designations: G protein-coupled receptor 39; MGC149541
Location: 2q21-q22
Annotation: Chromosome 2, NC_000002.11
The structure of the mammalian GPR39 gene contain two exons and one intron, which give origin to two transcripts (splice variants): GPR39-1a and GPR39-1b.
The position of the intron, located between TM5 and TM6, is also conserved among different species.
CHEMICAL STRUCTURE AND IMAGES
The human gpr39 gene encodes for a 453 aa polypeptide.
The primary structure of this receptor leads to the formation of a characteristic secondary structure, which defines his specific conformation.
The protein is then folded in a tertiary structure that contains different specific domains, which allows interactions with other molecules.
The GPR39 is a member of family A GPCRs with seven TMs connected by alternating extracellular loops (ELs) and intracellular loops (ILs). The N terminus is extracellular, and the C terminus is intracellular.
EXPRESSION AND REGULATION
GPR39 is here described to be expressed in a full-length, biologically active seven-transmembrane form, GPR39-1a, as well as in a truncated splice variant five-transmembrane form, GPR39-1b.
The structures of theGPR39 genes in human,mouse, zebrafish, and pufferfish were analyzed by comparison of the GPR39-1 cDNAsequence with the respective genome sequence. In all of these species, the GPR39 gene contains two exons and one intron, and the intron is located between TM5 and TM6.
Two GPR39 transcripts could be generated by alternatively splicing the same gene. The GPR39-1a transcript is generated by splicing away the intron and the GPR39-1b transcript is generated by retaining part of the intron.
The 3' exon of the GPR39 gene overlaps with an antisense gene called LYPD1 (Ly-6/PLAUR domain containing 1). Quantitative RT-PCR analysis demonstrated that GPR39-1a is expressed selectively throughout the gastrointestinal tract, including the liver and pancreas as well as in the kidney and
adipose tissue, whereas the truncated GPR39-1b form has a more broad expression pattern,
including the central nervous system but with highest expression in the stomach and small intestine.
In vivo experiments in rats demonstrated that GPR39 is up-regulated in adipose tissue during fasting
and in response to streptozotocin treatment, although its expression is kept constant in the liver
from the same animals. GPR39-1a was expressed in white but not brown adipose tissue and was down-regulated during adipocyte differentiation of fibroblasts. It is concluded that the transcriptional control mechanism, the tissue expression pattern, and in vivo response to physiological stimuli all indicate
that the GPR39 receptor very likely is of importance for the function of a number of metabolic
organs, including the liver, gastrointestinal tract, pancreas, and adipose tissue.
Interestingly, GPR39 was found to be a constitutively activated receptor acting mainly
through the serum response element (SRE) pathway
Although the endogenous ligand for GPR39 still remains to be ascertained, Zn2C
can activate GPR39 signaling through various pathways at micromolar concentrations.
GHRELIN RECEPTOR AND GPR39 DIFFERENCIES
GPR39 is an orphan 7TM receptor that is structurally and functionally related to the ghrelin receptor .
However, GPR39 has a broader signaling repertoire than that of the ghrelin receptor,
as it couples both to the G_q pathway with activation of phospholipase C, to the G_s with activation
of adenylate cyclase, and apparently also to G_12/13. Notably, like the ghrelin receptor, GPR39 is constitutively active;
accordingly, an increase in receptor expression will induce increased signaling, even without any ligand present . However, GPR39 signaling is stimulated by zinc ions, which may constitute a modulator of an
as yet unidentified, selective endogenous agonist.
In contrast to the ghrelin receptor, GPR39 is mainly expressed in peripheral tissues with important metabolic activity, such as the liver, the gastrointestinal tract, the endocrine pancreas, and adipose tissue.
GPR39 ROLES
GPR39 has previously been shown to modulate the function of the endocrine pancreas, as
GPR39-deficient mice displayed impaired glucose-stimulated insulin secretion both in vivo and in vitro
(for example, in isolated perifused islets), and their islets expressed decreased levels of the crucial transcription factors HNF-1a and PDX-1.
In addition, it has been demonstrated that GPR39 is important for gastric emptying,
gastric fluid secretion,and
gastrointestinal transit time.
The exact function of GPR39 in adipose tissue has not previously been characterized,
but the expression of GPR39 in white adipose tissue is up-regulated both during abstinence from food and in streptozotocin-induced diabetic rats.
In addition, it is known that mouse embryo fibroblasts capable of differentiating
into both white and brown adipocytes express high levels of GPR39,
and this expression is decreased by differentiation into both white and brown fat cells.
GPR39 KNOCK-OUT MOUSE
The receptor GPR39 is involved in the development of obesity. Significant increases in body weight
were observed in GPR39-deficient mice fed an HFD, where we observed an_2-fold increase in fat
mass compared with littermate control mice.
The fat accumulation was located both in the subcutaneous and in the visceral fat compartments.
The expected deregulation of the glucose homeostasis was observed, including increased fasting
glucose and insulin levels, as well as insulin resistance.
Analysis of adipose tissue from mice fed an HFD showed decreased expression and phosphorylation of
HSL and decreased expression was also observed for the other hormonally regulated lipase, ATGL.
In addition, the protein expression level of the accessory protein important for lipolysis, perilipin A,
was significantly lower in the GPR39-deficient mice compared with the WT mice.
Since one of the signaling pathways downstream of the adrenergic receptors involved in lipolysis,
ERK1/2, showed significantly decreasedphosphorylation levels in the GPR39-deficient mice,
it is suggested that GPR39 exerts its modulation of lipolysis through the same intracellular pathway as described previously for adrenergic receptors.
POSSIBILE THERAPEUTIC USE
The present data indicate that GPR39 is involved in the regulation of body weight and fat accumulation,
apparently through the modulation of intracellular signaling pathways and enzymes controlling lipolysis
and that the receptor is required for diet-induced thermogenesis. It is therefore tempting to suggest that
a GPR39 agonist would increase lipolysis and energy expenditure, especially under exposure to HFD,
and consequently would be an interesting novel antiobesity agent. However, the increased lipolysis may induce a chronically high level of circulating
fatty acids that correlates with adverse metabolic effects, such as insulin resistance. This would occur if fatty acids are
generated at a rate that exceeds the oxidative capacity, with consequent potential ectopic storage of triglycerides and increased insulin resistance.
Hence, partial stimulation of lipolysis, which is expected by stimulation of GPR39, in contrast to the adrenergic receptor, may provide an interesting novel target. Combined with the previous observation
that GPR39 stimulation improves the glucose-induced insulin secretion and maturation of pancreatic cells, this study indicates that GPR39 is an important novel drug target for the treatment of metabolic syndrome and obesity.
Authors
Federica Renna
Simona Ria
