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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
Signal transduction pathways of the four PGE receptor subtypes. EP1 is coupled to Gq/11 (Gq) and intracellular Ca2+ mobilization. EP2 and EP4 are coupled to the Gs/adenylyl cyclase/cAMP/protein kinase A (PKA) pathway. Recently, it was shown that the two receptors are also coupled to the β-arrestin (βArr)/Phosphoinositide 3-kinase (PI3-K) pathway. The EP3 receptor is mainly coupled to Gi, but in particular cell types, EP3 augments EP2/EP4-induced cAMP formation via the Gq/phospholipase C/Ca2+ pathway.
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fig04: Signal transduction pathways of the four PGE receptor subtypes. EP1 is coupled to Gq/11 (Gq) and intracellular Ca2+ mobilization. EP2 and EP4 are coupled to the Gs/adenylyl cyclase/cAMP/protein kinase A (PKA) pathway. Recently, it was shown that the two receptors are also coupled to the β-arrestin (βArr)/Phosphoinositide 3-kinase (PI3-K) pathway. The EP3 receptor is mainly coupled to Gi, but in particular cell types, EP3 augments EP2/EP4-induced cAMP formation via the Gq/phospholipase C/Ca2+ pathway.

Mentions: The EP1 receptor mediates the PGE2-induced elevation of free Ca2+ concentrations in CHO cells. This increase is dependent on extracellular Ca2+ and occurs without a detectable PI response, suggesting that EP1 regulates Ca2+ channel gating via an unidentified G protein.57) It was reported that EP1 expressed in Xenopus oocytes can couple to TRP5, a candidate for the receptor-activated Ca2+ channel (RACC), and this coupling is inhibited by an anti-sense oligonucleotide for Gq/G11 but not by one for Gi1 (Fig. 4).58) The EP2 and EP4 receptors couple to Gs and mediate increases in cAMP concentrations. The major signaling pathway of the EP3 receptor is inhibition of adenylate cyclase via Gi. It should be noted, however, that EP3 receptors do not couple exclusively to the pathways described but often to more than one G protein and signal transduction pathway. Hatae and Yamaoka found that when expressed in COS7 cells, the EP3 receptor elicits augmentation of EP2- or EP4-induced cAMP formation via Gq/11.59,60) Interestingly, this EP3-induced superactivation is observed irrespective of the C-terminal tail structure; EP3α, β, γ, which are the C-terminal splicing variants, and C-terminal-truncated mutant EP3 showed similar responses. Such coupling of EP3 to Gq/11 is dependent on lipid-raft structure. Localization of EP receptors to lipid raft microdomains may determine the cell-specific signal transduction pathway of EP3. In contrast, of interest is the presence of two EPs, EP2 and EP4, that are coupled to increases in cAMP. Nishigaki et al. found that EP4 shows higher sensitivity to agonist-induced desensitization than EP2.61) However, EP2 and EP4 apparently function redundantly in some processes. For example, both EP2 and EP4 mediate potentiation of Th17 expansion through cAMP–PKA signaling by PGE2, although the extent of the contribution by each receptor may be different.62) On the other hand, there are processes in which EP2 and EP4 play distinct roles. Some of these may be due to selective expression of either receptor in relevant cells such as the action of EP2 during cumulus expansion in ovulation and fertilization, and that of EP4 in closure of the ductus arteriosus (see 3.4.1).63,64) However, only EP4 stimulates IL-23 production from dendritic cells in mice, although both EP2 and EP4 are expressed in these cells.62) In 2003, Fujino et al. found that EP4 couples to PI3-kinase in addition to activation of adenylate cyclase.65) Later, Buchanan et al. demonstrated that EP4 activates PI3-K through activation of β-arrestin/Src pathway.66) Furthermore, we found that both EP2 and EP4 couple to PI3-kinase in naive T cells.62) Indeed, Chun et al. demonstrated that EP2 is also coupled to PI3-kinase via β-arrestin1 (Fig. 4).67)


Molecular biology of histidine decarboxylase and prostaglandin receptors.

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

Signal transduction pathways of the four PGE receptor subtypes. EP1 is coupled to Gq/11 (Gq) and intracellular Ca2+ mobilization. EP2 and EP4 are coupled to the Gs/adenylyl cyclase/cAMP/protein kinase A (PKA) pathway. Recently, it was shown that the two receptors are also coupled to the β-arrestin (βArr)/Phosphoinositide 3-kinase (PI3-K) pathway. The EP3 receptor is mainly coupled to Gi, but in particular cell types, EP3 augments EP2/EP4-induced cAMP formation via the Gq/phospholipase C/Ca2+ pathway.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: Signal transduction pathways of the four PGE receptor subtypes. EP1 is coupled to Gq/11 (Gq) and intracellular Ca2+ mobilization. EP2 and EP4 are coupled to the Gs/adenylyl cyclase/cAMP/protein kinase A (PKA) pathway. Recently, it was shown that the two receptors are also coupled to the β-arrestin (βArr)/Phosphoinositide 3-kinase (PI3-K) pathway. The EP3 receptor is mainly coupled to Gi, but in particular cell types, EP3 augments EP2/EP4-induced cAMP formation via the Gq/phospholipase C/Ca2+ pathway.
Mentions: The EP1 receptor mediates the PGE2-induced elevation of free Ca2+ concentrations in CHO cells. This increase is dependent on extracellular Ca2+ and occurs without a detectable PI response, suggesting that EP1 regulates Ca2+ channel gating via an unidentified G protein.57) It was reported that EP1 expressed in Xenopus oocytes can couple to TRP5, a candidate for the receptor-activated Ca2+ channel (RACC), and this coupling is inhibited by an anti-sense oligonucleotide for Gq/G11 but not by one for Gi1 (Fig. 4).58) The EP2 and EP4 receptors couple to Gs and mediate increases in cAMP concentrations. The major signaling pathway of the EP3 receptor is inhibition of adenylate cyclase via Gi. It should be noted, however, that EP3 receptors do not couple exclusively to the pathways described but often to more than one G protein and signal transduction pathway. Hatae and Yamaoka found that when expressed in COS7 cells, the EP3 receptor elicits augmentation of EP2- or EP4-induced cAMP formation via Gq/11.59,60) Interestingly, this EP3-induced superactivation is observed irrespective of the C-terminal tail structure; EP3α, β, γ, which are the C-terminal splicing variants, and C-terminal-truncated mutant EP3 showed similar responses. Such coupling of EP3 to Gq/11 is dependent on lipid-raft structure. Localization of EP receptors to lipid raft microdomains may determine the cell-specific signal transduction pathway of EP3. In contrast, of interest is the presence of two EPs, EP2 and EP4, that are coupled to increases in cAMP. Nishigaki et al. found that EP4 shows higher sensitivity to agonist-induced desensitization than EP2.61) However, EP2 and EP4 apparently function redundantly in some processes. For example, both EP2 and EP4 mediate potentiation of Th17 expansion through cAMP–PKA signaling by PGE2, although the extent of the contribution by each receptor may be different.62) On the other hand, there are processes in which EP2 and EP4 play distinct roles. Some of these may be due to selective expression of either receptor in relevant cells such as the action of EP2 during cumulus expansion in ovulation and fertilization, and that of EP4 in closure of the ductus arteriosus (see 3.4.1).63,64) However, only EP4 stimulates IL-23 production from dendritic cells in mice, although both EP2 and EP4 are expressed in these cells.62) In 2003, Fujino et al. found that EP4 couples to PI3-kinase in addition to activation of adenylate cyclase.65) Later, Buchanan et al. demonstrated that EP4 activates PI3-K through activation of β-arrestin/Src pathway.66) Furthermore, we found that both EP2 and EP4 couple to PI3-kinase in naive T cells.62) Indeed, Chun et al. demonstrated that EP2 is also coupled to PI3-kinase via β-arrestin1 (Fig. 4).67)

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