The EP4 prostanoid receptor is one of four receptor subtypes for prostaglandin E2. It belongs to the family of G protein-coupled receptors. It was originally identified, similar to the EP2 receptor ...as a G(s)α-coupled, adenylyl cyclase-stimulating receptor. EP4 signaling plays a variety of roles through cAMP effectors, i.e., protein kinase A and exchange protein activated by cAMP. However, emerging evidence from studies using pharmacological approaches and genetically modified mice suggests that EP4, unlike EP2, can also be coupled to G(i)α, phosphatidylinositol 3-kinase, β-arrestin, or β-catenin. These signaling pathways constitute unique roles for the EP4 receptor. EP4 is widely distributed in the body and thus plays various physiologic and pathophysiologic roles. In particular, EP4 signaling is closely related to carcinogenesis, cardiac hypertrophy, vasodilation, vascular remodeling, bone remodeling, gastrointestinal homeostasis, renal function, and female reproductive function. In addition to the classic anti-inflammatory action of EP4 on mononuclear cells and T cells, recent evidence has shown that EP4 signaling contributes to proinflammatory action as well. The aim of this review is to present current findings on the biologic functions of the EP4 receptor. In particular, we will discuss its diversity from the standpoint of EP4-mediated signaling.
The fact that Snow did not sneak into “red China" to gather information constituting the basis of his Red Start over China all alone is in many instances misunderstood even by scholars.Mao Zedong’s ...biography has been the subject of an international mountain of commentary in China and elsewhere. Biographies praising Mao and those slandering him are all based on the American journalist Edgar Snow’s (1905–1972) account in Red Star over China for the route Mao traveled from early childhood through his youth.How the “Red Star" Rose introduces the image of Mao and the biographical information made known to the world through the publication of Red Star, and with its publication the circumstances which they fundamentally undermined. Ishikawa Yoshihiro uses Mao Zedong as raw material to examine from whence and how ordinary historical information and images which we habitually use unconsciously come into being. He desires to help readers to reconsider the historicity of the generation of not only Mao’s image but of that of “historical materials."---With a title that evokes Gao Hua’s seminal study of Mao Zedong’s rise in the Chinese Communist Party, Ishikawa Yoshihiro asks two critical questions—What did the world know of Mao before the publication of Edgar Snow’s Red Star over China? How did Red Star change that understanding? With the meticulous research, careful documentation, and fair-minded judgment that characterizes all of Ishikawa’s work, he shows how little even Moscow and the Communist International knew about Mao before 1936. This study is full of unexpected insights into the origins of early visual images of Mao, the background to Snow’s historic trip to northern Shaanxi, and the evolution of the classic study that he left. In a world where balanced judgment of the rise of Mao is increasingly difficult to find, Ishikawa’s scholarship stands out as a rare model of judicious balance.—Joseph W. Esherick, Emeritus Professor, Hwei-chih and Julia Hsiu Chair in Chinese Studies, University of California, San DiegoThis book is, first, an exquisite excavation on the enabling infrastructures in the writing and publishing of one of the most iconic works in journalistic interviews in the 20th century, a text that broke through a wall of intelligence blockade to give to the world, in an autobiographical voice and with a striking image, the debut of the revolutionary Mao while holed up in a mountain base area. It is, in addition, a history of the reading of the book in multiple languages including Chinese that is indexed to the rise of the Mao cult thereafter. Ishikawa captures a moment of a past gearing up in anticipation of a future that never came. This book is a must-read for all with an interest in Mao, journalism, and the history of books.—Wen-hsin Yeh, Richard H. and Laurie C. Morrison Chair Professor in History, University of California, BerkeleyIshikawa offers a challenging reflection on how historical information and images that we take for granted come into being through the twin case studies of images of Mao Zedong before Edgar Snow’s famous biography in 1936 and then how Snow’s images of Mao were translated, and transmuted, into Chinese, Russian and Japanese. Joshua Fogel’s careful translation brings this impeccable example of Japanese sinology to the English reading public. —Timothy Cheek, Professor and Louis Cha Chair in Chinese Research, University of British Columbia
Intracellular calcium (Ca
) signaling regulates many cellular functions, including cell proliferation and migration, in both normal cells and cancer cells. Store-operated Ca
entry (SOCE) is a major ...mechanism by which Ca
is imported from the extracellular space to the intracellular space, especially in nonexcitable cells. Store-operated Ca
entry (SOCE) is also a receptor-regulated Ca
entry pathway that maintains Ca
homeostasis by sensing reduced Ca
levels in the endoplasmic reticulum (ER). In general, the activation of G protein-coupled receptors (GPCRs) or immunoreceptors, such as T-cell, B-cell and Fc receptors, results in the production of inositol 1,4,5-trisphosphate (IP
). IP
binds to IP
receptors located in the ER membrane. The, IP
receptors in the ER membrane trigger a rapid and transient release of Ca
from the ER store. The resulting depletion of ER Ca
concentrations is sensed by the EF-hand motif of stromal interaction molecule (STIM), i.e., calcium sensor, which then translocates to the plasma membrane (PM). STIM interacts with Orai Ca
channel subunits (also known as CRACM1) on the PM, leading to Ca
influx from the extracellular space to increase intracellular Ca
concentrations. The physiological functions of Orai and STIM have been studied mainly with respect to their roles in the immune system. Based on numerous previous studies, Orai channels (Orai1, Orai2 and Orai3 channels) control Ca
release-activated Ca
(CRAC) currents and contribute to SOCE currents in other types of cells, including various cancer cells. There are many reports that Orai1 is involved in cell proliferation, migration, metastasis, apoptosis and epithelial-mesenchymal transition (EMT) in various cancers. We previously found that Orai1 plays important roles in cell apoptosis and migration in melanoma. Recently, we reported novel evidence of Orai1 in human oral squamous cell carcinoma (OSCC) cells and human cardiac fibroblasts (HCFs). In this review, we present multiple physiological functions of Orai1 in various cancer cells and cardiac fibroblasts, including our findings.
Extracellular matrix (ECM) proteins are biosynthesized in the rough endoplasmic reticulum (rER) and transported via the Golgi apparatus to the extracellular space. The coat protein complex II (COPII) ...transport vesicles are approximately 60–90 nm in diameter. However, several ECM molecules are much larger, up to several hundreds of nanometers. Therefore, special COPII vesicles are required to coat and transport these molecules. Transmembrane Protein Transport and Golgi Organization 1 (TANGO1) facilitates loading of collagens into special vesicles. The Src homology 3 (SH3) domain of TANGO1 was proposed to recognize collagen molecules, but how the SH3 domain recognizes various types of collagen is not understood. Moreover, how are large noncollagenous ECM molecules transported from the rER to the Golgi? Here we identify heat shock protein (Hsp) 47 as a guide molecule directing collagens to special vesicles by interacting with the SH3 domain of TANGO1. We also consider whether the collagen secretory model applies to other large ECM molecules.
Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix, in particular, collagens. Two IPF therapeutics, nintedanib and pirfenidone, decelerate lung ...function decline, but their underlying mechanisms of action are poorly understood. In this study, we sought to analyze their effects on collagen synthesis and maturation at important regulatory levels. Primary human fibroblasts from patients with IPF and healthy donors were treated with nintedanib (0.01-1.0 μM) or pirfenidone (100-1,000 μM) in the absence or presence of transforming growth factor-β1. Effects on collagen, fibronectin, FKBP10, and HSP47 expression, and collagen I and III secretion, were analyzed by quantitative polymerase chain reaction and Western blot. The appearance of collagen fibrils was monitored by scanning electron microscopy, and the kinetics of collagen fibril assembly was assessed using a light-scattering approach. In IPF fibroblasts, nintedanib reduced the expression of collagen I and V, fibronectin, and FKBP10 and attenuated the secretion of collagen I and III. Pirfenidone also down-regulated collagen V but otherwise showed fewer and less pronounced effects. By and large, the effects were similar in donor fibroblasts. For both drugs, electron microscopy of IPF fibroblast cultures revealed fewer and thinner collagen fibrils compared with untreated controls. Finally, both drugs dose-dependently delayed fibril formation of purified collagen I. In summary, both drugs act on important regulatory levels in collagen synthesis and processing. Nintedanib was more effective in down-regulating profibrotic gene expression and collagen secretion. Importantly, both drugs inhibited collagen I fibril formation and caused a reduction in and an altered appearance of collagen fibril bundles, representing a completely novel mechanism of action for both drugs.
Collagen is the most abundant protein in the extracellular matrix in humans and is critical to the integrity and function of many musculoskeletal tissues. A molecular ensemble comprising more than 20 ...molecules is involved in collagen biosynthesis in the rough endoplasmic reticulum. Two proteins, heat shock protein 47 (Hsp47/SERPINH1) and 65-kDa FK506-binding protein (FKBP65/FKBP10), have been shown to play important roles in this ensemble. In humans, autosomal recessive mutations in both genes cause similar osteogenesis imperfecta phenotypes. Whereas it has been proposed that Hsp47 and FKBP65 interact in the rough endoplasmic reticulum, there is neither clear evidence for this interaction nor any data regarding their binding affinities for each other. In this study using purified endogenous proteins, we examined the interaction between Hsp47, FKBP65, and collagen and also determined their binding affinities and functions in vitro. Hsp47 and FKBP65 show a direct but weak interaction, and FKBP65 prefers to interact with Hsp47 rather than type I collagen. Our results suggest that a weak interaction between Hsp47 and FKBP65 confers mutual molecular stability and also allows for a synergistic effect during collagen folding. We also propose that Hsp47 likely acts as a hub molecule during collagen folding and secretion by directing other molecules to reach their target sites on collagens. Our findings may explain why osteogenesis imperfecta-causing mutations in both genes result in similar phenotypes.
The heart works as a driving force to deliver oxygen and nutrients to the whole body. Interrupting this function for only several minutes can cause critical and permanent damage to the human body. ...Thus, heart failure (HF) or attenuated cardiac function is an important factor that affects both patient's the quality of life and longevity. Numerous clinical and basic studies have been performed to clarify the complex pathophysiology of HF and to develop effective therapies. Modulating the β-adrenergic receptor-mediated signaling pathway has been one of the most crucial targets for HF therapy. Impressively, recent reports identified p53, a well-known tumor suppressor, as a major player in the development of HF. The present review highlights the apoptosis of cardiomyocytes, which is one of the important mechanisms that leads to HF and can be induced by both β-adrenergic signaling and p53. Consideration of the cross-talk among these major pathways will be important when developing effective and safe therapies for HF. (Circ J 2011; 75: 1811-1818)
Coarctation of the aorta (CoA) is defined as a congenital stenosis of the thoracic aorta and is one of the most common congenital cardiovascular diseases. Despite successful surgical treatment for ...CoA, arterial abnormalities, including refractory hypertension, aortic aneurysm, and proatherogenic phenotypic changes, frequently affect patients' quality of life. Emerging evidence from morphological and molecular biological investigations suggest that the area of CoA is characterized by phenotypic modulation of smooth muscle cells, intimal thickening, and impaired elastic fiber formation. These changes extend to the pre-and post-stenotic aorta and impair arterial elasticity. The aim of this review is to present current findings on the pathology and molecular mechanisms of vascular remodeling due to CoA. In particular, we will discuss the association between CoA and the ductus arteriosus since the most common site for the stenosis is in the proximity of the ductus arteriosus.
Background: It has been suggested that protein directly activated by cAMP (Epac), one of the downstream signaling molecules of β-adrenergic receptor (β-AR), may be an effective target for the ...treatment of arrhythmia. However, there have been no reports on the anti-arrhythmic effects or cardiac side-effects of Epac1 inhibitors in vivo. Methods and Results: In this study, the roles of Epac1 in the development of atrial and ventricular arrhythmias are examined. In addition, we examined the usefulness of CE3F4, an Epac1-selective inhibitor, in the treatment of the arrhythmias in mice. In Epac1 knockout (Epac1-KO) mice, the duration of atrial fibrillation (AF) was shorter than in wild-type mice. In calsequestrin2 knockout mice, Epac1 deficiency resulted in a reduction of ventricular arrhythmia. In both atrial and ventricular myocytes, sarcoplasmic reticulum (SR) Ca2+ leak, a major trigger of arrhythmias, and spontaneous SR Ca2+ release (SCR) were attenuated in Epac1-KO mice. Consistently, CE3F4 treatment significantly prevented AF and ventricular arrhythmia in mice. In addition, the SR Ca2+ leak and SCR were significantly inhibited by CE3F4 treatment in both atrial and ventricular myocytes. Importantly, cardiac function was not significantly affected by a dosage of CE3F4 sufficient to exert anti-arrhythmic effects. Conclusions: These findings indicated that Epac1 is involved in the development of atrial and ventricular arrhythmias. CE3F4, an Epac1-selective inhibitor, prevented atrial and ventricular arrhythmias in mice.
The biosynthesis of collagens occurs in the rough endoplasmic reticulum and requires a large numbers of molecular chaperones, foldases, and post-translational modification enzymes. Collagens contain ...a large number of proline residues that are post-translationally modified to 3-hydroxyproline or 4-hydroxyproline, and the rate-limiting step in formation of the triple helix is the cis-trans isomerization of peptidyl-proline bonds. This step is catalyzed by peptidyl-prolyl cis-trans isomerases. There are seven peptidyl-prolyl cis-trans isomerases in the rER, and so far, two of these enzymes, cyclophilin B and FKBP65, have been shown to be involved in collagen biosynthesis. The absence of either cyclophilin B or FKBP65 leads to a recessive form of osteogenesis imperfecta. The absence of FKBP22 leads to a kyphoscoliotic type of Ehlers-Danlos syndrome (EDS), and this type of EDS is classified as EDS type VI, which can also be caused by a deficiency in lysyl-hydroxylase 1. However, the lack of FKBP22 shows a wider spectrum of clinical phenotypes than the absence of lysyl-hydroxylase 1 and additionally includes myopathy, hearing loss, and aortic rupture. Here we show that FKBP22 catalyzes the folding of type III collagen and interacts with type III collagen, type VI collagen, and type X collagen, but not with type I collagen, type II collagen, or type V collagen. These restrictive interactions might help explain the broader phenotype observed in patients that lack FKBP22.
Background: Procollagen biosynthesis requires a large number of foldases, chaperones, and modifying enzymes.
Results: FKBP22 is a foldase and chaperone that interacts with a subset of collagens.
Conclusion: Collagen type-specific chaperones and foldases exist in the rER.
Significance: The lack of collagen type-specific rER proteins can lead to broader or overlapping phenotypes of connective tissue disorders.
PDF
