Lin DC, et al 2002 reported the identification and Molecular Characterization of Two Closely
Related G Protein-coupled Receptors Activated by
Prokineticins/Endocrine Gland Vascular Endothelial Growth
Factor.The atuhotrs previously described two mammalian secreted proteins, prokineticin 1 and
prokineticin 2, that potently contract gastrointestinal smooth muscle. Prokineticin 1
has also been shown to promote angiogenesis by stimulating proliferation, migration,
and fenestration of endocrine organ-derived endothelial cells. The authors now report the
cloning and characterization of two closely related G protein-coupled receptors as
receptors for prokineticins. Expression of prokineticin receptors in heterologous
systems shows that these receptors bind to and are activated by nanomolar
concentrations of recombinant prokineticins. Activation of prokineticin receptors
leads to mobilization of calcium, stimulation of phosphoinositide turnover, and
activation of p44/p42 MAPK signaling pathways that are consistent with the effects of
prokineticins on smooth muscle contraction and angiogenesis. mRNA expression
analysis reveals that prokineticin receptors are expressed in gastrointestinal organs,
endocrine glands, and other tissues. In particular, PKR2 is expressed at high levels in the ovary. Cheng MY,et al 2002 reported that Prokineticin 2 transmits the behavioural circadian rhythm of the
suprachiasmatic nucleus.
NCBI Summary:
Prokineticins are secreted proteins that can promote angiogenesis and induce strong gastrointestinal smooth muscle contraction. The protein encoded by this gene is an integral membrane protein and G protein-coupled receptor for prokineticins. The encoded protein is similar in sequence to GPR73, another G protein-coupled receptor for prokineticins.
General function
Receptor
Comment
Cellular localization
Plasma membrane
Comment
Ovarian function
Follicle development, Luteinization
Comment
PROKINETICINS (ENDOCRINE GLAND-VEGF AND BV8) IN THE BOVINE OVARY: EXPRESSION AND ROLE AS MITOGENS AND SURVIVAL FACTORS FOR CORPUS LUTEUM DERIVED- ENDOTHELIAL CELLS Kisliouk T, et al .
A highly vascular endocrine gland, the corpus luteum (CL) is an excellent model for the study of angiogenic factors. Prokineticins (PK-1 and 2), also termed endocrine-gland-derived VEGF and BV8 are newly identified proteins described as selective angiogenic mitogens. We previously identified PK binding sites - two closely homologous G protein-coupled receptors (PK-R1 and PK-R2) in human and bovine ovarian cells, but their function remained unknown. In this study we examined the presence and effects of PKsin CL-derived endothelial and steroidogenic cell types (LEC and LSC, respectively). PK-1 mRNA were identified in CL and follicles by real-time PCR, using primers specific for the bovine PK-1 sequence (retrieved from Bos taurus whole genome shotgun database). PKs were potent angiogenic mitogens for LEC: they enhanced cell proliferation, elevated [(3)H]-thymidine incorporation, MAPK activation and c-jun/fos mRNA expression. The effects of PK proteins on cell survival were examined by nuclear morphology (DAPI staining), measurement of DNA fragmentation (TUNEL assay) and caspase-3 cleavage. Results obtained by these techniques demonstrated that PKs protected LEC from serum starvation-induced apoptosis. Stress conditions such as serum withdrawal, TNFalpha and hypoxia markedly increased PK-R2 expression, whereas mRNA levels of PK-R1 remained unchanged. These suggest that the anti-apoptotic effect of PK-1 on LEC may be mediated via PK-R2. PK-1 increased VEGF mRNA expression by LSC implying that it could also indirectly, via VEGF, affect luteal angiogenesis. Together, these findings suggest an important role for PK-1 in luteal function by acting as a mitogen and survival factor in LEC.
Expression regulated by
Comment
Ovarian localization
Luteal cells
Comment
Follicle stages
Corpus luteum
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Matsumoto S et al. Prokineticins, multifunctional secreted proteins, activate two endogenous G protein-coupled receptors PKR1 and PKR2. From in situ analysis of the mouse brain, we discovered that PKR2 is predominantly expressed in the olfactory bulb (OB). To examine the role of PKR2 in the OB, we created PKR1- and PKR2-gene-disrupted mice (Pkr1(-/-) and Pkr2(-/-), respectively). Phenotypic analysis indicated that not Pkr1(-/-)but Pkr2(-/-)mice exhibited hypoplasia of the OB. This abnormality was observed in the early developmental stages of fetal OB in the Pkr2(-/-) mice. In addition, the Pkr2(-/-) mice showed severe atrophy of the reproductive system, including the testis, ovary, uterus, vagina, and mammary gland. In the Pkr2(-/-) mice, the plasma levels of testosterone and follicle-stimulating hormone were decreased, and the mRNA transcription levels of gonadotropin-releasing hormone in the hypothalamus and luteinizing hormone and follicle-stimulating hormone in the pituitary were also significantly reduced. Immunohistochemical analysis revealed that gonadotropin-releasing hormone neurons were absent in the hypothalamus in the Pkr2(-/-) mice. The phenotype of the Pkr2(-/-) mice showed similarity to the clinical features of Kallmann syndrome, a human disease characterized by association of hypogonadotropic hypogonadism and anosmia. Our current findings demonstrated that physiological activation of PKR2 is essential for normal development of the OB and sexual maturation.