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Molecular biology of histidine decarboxylase and prostaglandin receptors.

Ichikawa A, Sugimoto Y, Tanaka S - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

Bottom Line: For the precise understanding of the physiological roles of histamine and PGs, it is necessary to clarify the molecular mechanisms involved in their synthesis as well as their receptor-mediated responses.We then characterized the expression patterns and functions of these genes.We have here summarized our research, which should contribute to progress in the molecular biology of HDC and PG receptors.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan. aichikaw@mukogawa-u.ac.jp

ABSTRACT
Histamine and prostaglandins (PGs) play a variety of physiological roles as autacoids, which function in the vicinity of their sources and maintain local homeostasis in the body. They stimulate target cells by acting on their specific receptors, which are coupled to trimeric G proteins. For the precise understanding of the physiological roles of histamine and PGs, it is necessary to clarify the molecular mechanisms involved in their synthesis as well as their receptor-mediated responses. We cloned the cDNAs for mouse L-histidine decarboxylase (HDC) and 6 mouse prostanoid receptors (4 PGE(2) receptors, PGF receptor, and PGI receptor). We then characterized the expression patterns and functions of these genes. Furthermore, we established gene-targeted mouse strains for HDC and PG receptors to explore the novel pathophysiological roles of histamine and PGs. We have here summarized our research, which should contribute to progress in the molecular biology of HDC and PG receptors.

Show MeSH
Schematic model of the roles of PGE2–EP2 signaling in cumulus ECM status and successful fertilization. Gonadotropins stimulate secretion of extracellular matrix (ECM) components such as hyaluronan from cumulus cells. Ovulation-associated signals induce the gene expression and production of chemokines such as CCL7 in cumulus cells. CCL7 stimulates cumulus ECM protein assembly to protect the oocyte in an autocrine manner, and facilitates sperm migration to cumulus–oocyte complexes. Once the complexes reach the fertilization site, PGE2/EP2/cAMP signaling down-regulates such chemokine actions on the cumuli so that chemokine signaling does not interfere with sperm penetration.
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fig07: Schematic model of the roles of PGE2–EP2 signaling in cumulus ECM status and successful fertilization. Gonadotropins stimulate secretion of extracellular matrix (ECM) components such as hyaluronan from cumulus cells. Ovulation-associated signals induce the gene expression and production of chemokines such as CCL7 in cumulus cells. CCL7 stimulates cumulus ECM protein assembly to protect the oocyte in an autocrine manner, and facilitates sperm migration to cumulus–oocyte complexes. Once the complexes reach the fertilization site, PGE2/EP2/cAMP signaling down-regulates such chemokine actions on the cumuli so that chemokine signaling does not interfere with sperm penetration.

Mentions: E- and F-type PGs are implicated in many aspects of reproductive functions. These include not only peripheral reproductive processes but also gonadotropin secretion in the central nervous system. To date, it has been accepted that luteinizing hormone-releasing hormone (LHRH) is secreted by the hypothalamus in response to PGE2. Although it was revealed that estradiol treatment is followed by increased expression of EP1 and EP3 mRNAs in LHRH neurons, no apparent changes were found in serum concentrations of LH and FSH in female mice of the COX-1- and COX-2-knockouts.88) In the ovary, the PG content of follicles increases as the follicles mature. Indomethacin abolishes LH-induced ovulation, and this effect is reversed by treatment with PGE2 or PGF2α.89) Studies on mice deficient in COX-2, but not COX-1, showed multiple reproductive failures in early pregnancy, such as ovulation, fertilization, implantation, and decidualization, suggesting that PGs play essential roles in these processes.90) Since IP-, EP1-, EP3-, EP4-, and TP-deficient females are fertile, these receptors may be dispensable in female reproduction. Likewise, ovulation, fertilization and implantation are normal in mice lacking the FP receptor gene, suggesting that PGF2α is not crucial for these processes.84) We reported a failure in early pregnancy in EP2-deficient female mice.63) We found that EP2-deficient female mice consistently deliver fewer pups than their wild-type counterparts irrespective of the genotypes of the mating males. We detected slightly impaired ovulation and dramatic reduction in fertilization in EP2-deficient mice and concluded that failure in early pregnancy in COX-2-deficient mice is at least in part due to dysfunction of the EP2 receptor. We further found that this phenotype is due to impaired expansion of the cumulus oophorus. To obtain insight into the mechanism causing fertilization failure in the EP2-deficient cumulus, we compared the gene expression profiles of wild-type and EP2- cumuli isolated from the oviduct ampulla.91,92) We found increased gene expression of chemokines such as ccl2, ccl7 and ccl9 in EP2-deficient cumuli compared with those of wild-type. Furthermore, we molecularly dissected the functional consequences of enhanced chemokine signaling in EP2-mutated cumuli, and found that chemokine signaling facilitates both sperm attraction to the cumulus and compaction of the cumulus by integrin-mediated extracellular matrix assembly, the latter of which is down-regulated by PGE2-EP2 signaling to allow sperm penetration for successful fertilization (Fig. 7).


Molecular biology of histidine decarboxylase and prostaglandin receptors.

Ichikawa A, Sugimoto Y, Tanaka S - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

Schematic model of the roles of PGE2–EP2 signaling in cumulus ECM status and successful fertilization. Gonadotropins stimulate secretion of extracellular matrix (ECM) components such as hyaluronan from cumulus cells. Ovulation-associated signals induce the gene expression and production of chemokines such as CCL7 in cumulus cells. CCL7 stimulates cumulus ECM protein assembly to protect the oocyte in an autocrine manner, and facilitates sperm migration to cumulus–oocyte complexes. Once the complexes reach the fertilization site, PGE2/EP2/cAMP signaling down-regulates such chemokine actions on the cumuli so that chemokine signaling does not interfere with sperm penetration.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3037517&req=5

fig07: Schematic model of the roles of PGE2–EP2 signaling in cumulus ECM status and successful fertilization. Gonadotropins stimulate secretion of extracellular matrix (ECM) components such as hyaluronan from cumulus cells. Ovulation-associated signals induce the gene expression and production of chemokines such as CCL7 in cumulus cells. CCL7 stimulates cumulus ECM protein assembly to protect the oocyte in an autocrine manner, and facilitates sperm migration to cumulus–oocyte complexes. Once the complexes reach the fertilization site, PGE2/EP2/cAMP signaling down-regulates such chemokine actions on the cumuli so that chemokine signaling does not interfere with sperm penetration.
Mentions: E- and F-type PGs are implicated in many aspects of reproductive functions. These include not only peripheral reproductive processes but also gonadotropin secretion in the central nervous system. To date, it has been accepted that luteinizing hormone-releasing hormone (LHRH) is secreted by the hypothalamus in response to PGE2. Although it was revealed that estradiol treatment is followed by increased expression of EP1 and EP3 mRNAs in LHRH neurons, no apparent changes were found in serum concentrations of LH and FSH in female mice of the COX-1- and COX-2-knockouts.88) In the ovary, the PG content of follicles increases as the follicles mature. Indomethacin abolishes LH-induced ovulation, and this effect is reversed by treatment with PGE2 or PGF2α.89) Studies on mice deficient in COX-2, but not COX-1, showed multiple reproductive failures in early pregnancy, such as ovulation, fertilization, implantation, and decidualization, suggesting that PGs play essential roles in these processes.90) Since IP-, EP1-, EP3-, EP4-, and TP-deficient females are fertile, these receptors may be dispensable in female reproduction. Likewise, ovulation, fertilization and implantation are normal in mice lacking the FP receptor gene, suggesting that PGF2α is not crucial for these processes.84) We reported a failure in early pregnancy in EP2-deficient female mice.63) We found that EP2-deficient female mice consistently deliver fewer pups than their wild-type counterparts irrespective of the genotypes of the mating males. We detected slightly impaired ovulation and dramatic reduction in fertilization in EP2-deficient mice and concluded that failure in early pregnancy in COX-2-deficient mice is at least in part due to dysfunction of the EP2 receptor. We further found that this phenotype is due to impaired expansion of the cumulus oophorus. To obtain insight into the mechanism causing fertilization failure in the EP2-deficient cumulus, we compared the gene expression profiles of wild-type and EP2- cumuli isolated from the oviduct ampulla.91,92) We found increased gene expression of chemokines such as ccl2, ccl7 and ccl9 in EP2-deficient cumuli compared with those of wild-type. Furthermore, we molecularly dissected the functional consequences of enhanced chemokine signaling in EP2-mutated cumuli, and found that chemokine signaling facilitates both sperm attraction to the cumulus and compaction of the cumulus by integrin-mediated extracellular matrix assembly, the latter of which is down-regulated by PGE2-EP2 signaling to allow sperm penetration for successful fertilization (Fig. 7).

Bottom Line: For the precise understanding of the physiological roles of histamine and PGs, it is necessary to clarify the molecular mechanisms involved in their synthesis as well as their receptor-mediated responses.We then characterized the expression patterns and functions of these genes.We have here summarized our research, which should contribute to progress in the molecular biology of HDC and PG receptors.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan. aichikaw@mukogawa-u.ac.jp

ABSTRACT
Histamine and prostaglandins (PGs) play a variety of physiological roles as autacoids, which function in the vicinity of their sources and maintain local homeostasis in the body. They stimulate target cells by acting on their specific receptors, which are coupled to trimeric G proteins. For the precise understanding of the physiological roles of histamine and PGs, it is necessary to clarify the molecular mechanisms involved in their synthesis as well as their receptor-mediated responses. We cloned the cDNAs for mouse L-histidine decarboxylase (HDC) and 6 mouse prostanoid receptors (4 PGE(2) receptors, PGF receptor, and PGI receptor). We then characterized the expression patterns and functions of these genes. Furthermore, we established gene-targeted mouse strains for HDC and PG receptors to explore the novel pathophysiological roles of histamine and PGs. We have here summarized our research, which should contribute to progress in the molecular biology of HDC and PG receptors.

Show MeSH