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Physiological Importance (physiological + importance)
Selected AbstractsReduced fertility of mouse epididymal sperm lacking Prss21/Tesp5 is rescued by sperm exposure to uterine microenvironmentGENES TO CELLS, Issue 10 2008Misuzu Yamashita Although the acrosome reaction and subsequent penetration of sperm through the egg zona pellucida (ZP) are essential for mammalian fertilization, the molecular mechanism is still controversial. We have previously identified serine protease Tesp5 identical to Prss21 on the mouse sperm surface as a candidate enzyme involved in sperm penetration through the ZP. Here we show that despite normal fertility of male mice lacking Prss21/Tesp5, the epididymal sperm penetrates the ZP only at a very low rate in vitro, presumably owing to the reduced ability to bind the ZP and undergo the ZP-induced acrosome reaction. The ability of Prss21-null sperm to fuse with the egg in vitro was also impaired severely. Intriguingly, the reduced fertility of Prss21-null epididymal sperm was rescued by exposure of the sperm to the uterine microenvironment and by in vitro treatment of the sperm with uterine fluids. These data suggest the physiological importance of sperm transport through the uterus. [source] Membrane-bound and cytosolic forms of heterotrimeric G proteins in young and adult rat myocardium: Influence of neonatal hypo- and hyperthyroidismJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2001Jiri Novotny Abstract Membrane and cytosolic fractions prepared from ventricular myocardium of young (21-day-old) hypo- or hyperthyroid rats and adult (84-day-old) previously hypo- or hyperthyroid rats were analyzed by immunoblotting with specific anti-G-protein antibodies for the relative content of Gs,, Gi,/Go,, Gq,/G11,, and G,. All tested G protein subunits were present not only in myocardial membranes but were at least partially distributed in the cytosol, except for Go,2, and G11,. Cytosolic forms of the individual G proteins represented about 5,60% of total cellular amounts of these proteins. The long (Gs,-L) isoform of Gs, prevailed over the short (Gs,-S) isoform in both crude myocardial membranes and cytosol. The Gs,-L/Gs,-S ratio in membranes as well as in cytosol increased during maturation due to a substantial increase in Gs,-L. Interestingly, whereas the amount of membrane-bound Gi,/Go, and Gq,/G11, proteins tend to lower during postnatal development, cytosolic forms of these G proteins mostly rise. Neonatal hypothyroidism reduced the amount of myocardial Gs, and increased that of Gi,/Go, proteins. By contrast, neonatal hyperthyroidism increased expression of Gs, and decreased that of Gi, and G11, in young myocardium. Changes in G protein content induced by neonatal hypo- and hyperthyroidism in young rat myocardium were restored in adulthood. Alterations in the membrane-cytosol balance of G protein subunits associated with maturation or induced by altered thyroid status indicate physiological importance of cytosolic forms of these proteins in the rat myocardium. J. Cell. Biochem. 82: 215,224, 2001. © 2001 Wiley-Liss, Inc. [source] Pharmaceutical and pharmacological importance of peptide transportersJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2008Matthias Brandsch Peptide transport is currently a prominent topic in membrane research. The transport proteins involved are under intense investigation because of their physiological importance in protein absorption and also because peptide transporters are possible vehicles for drug delivery. Moreover, in many tissues peptide carriers transduce peptidic signals across membranes that are relevant in information processing. The focus of this review is on the pharmaceutical relevance of the human peptide transporters PEPT1 and PEPT2. In addition to their physiological substrates, both carriers transport many ,-lactam antibiotics, valaciclovir and other drugs and prodrugs because of their sterical resemblance to di- and tripeptides. The primary structure, tissue distribution and substrate specificity of PEPT1 and PEPT2 have been well characterized. However, there is a dearth of knowledge on the substrate binding sites and the three-dimensional structure of these proteins. Until this pivotal information becomes available by X-ray crystallography, the development of new drug substrates relies on classical transport studies combined with molecular modelling. In more than thirty years of research, data on the interaction of well over 700 di- and tripeptides, amino acid and peptide derivatives, drugs and prodrugs with peptide transporters have been gathered. The aim of this review is to put the reports on peptide transporter-mediated drug uptake into perspective. We also review the current knowledge on pharmacogenomics and clinical relevance of human peptide transporters. Finally, the reader's attention is drawn to other known or proposed human peptide-transporting proteins. [source] The rediscovery and isolation of TFPIJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 8 2003G. J. Broze Jr Summary., Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type proteinase inhibitor that produces factor (F)Xa-dependent feedback inhibition of the factor VIIa/tissue factor (FVIIa/TF) catalytic complex that is responsible for the initiation of coagulation. Since 1985, when Rapaport and colleagues reported that the lipoprotein fraction of plasma contained a FXa-dependent inhibitor of FVIIa/TF, myriad articles have established its biochemical structure, its mechanism of action, and its physiological importance. This brief personal account reviews historical studies that established the existence of the inhibitor and the events that led to its initial isolation. [source] GIGANTEA is a component of a regulatory pathway determining wall ingrowth deposition in phloem parenchyma transfer cells of Arabidopsis thalianaTHE PLANT JOURNAL, Issue 4 2010Joshua Edwards Summary Transfer cells are specialised transport cells containing invaginated wall ingrowths that generate an amplified plasma membrane surface area with high densities of transporter proteins. They trans -differentiate from differentiated cells at sites at which enhanced rates of nutrient transport occur across apo/symplasmic boundaries. Despite their physiological importance, little is known of the molecular mechanisms regulating construction of their intricate wall ingrowths. We investigated the genetic control of wall ingrowth formation in phloem parenchyma transfer cells of leaf minor veins in Arabidopsis thaliana. Wall ingrowth development in these cells is substantially enhanced upon exposing plants to high-light or cold treatments. A hierarchical bioinformatic analysis of public microarray datasets derived from the leaves of plants subjected to these treatments identified GIGANTEA (GI) as one of 46 genes that are commonly up-regulated twofold or more under both high-light and cold conditions. Histological analysis of the GI mutants gi-2 and gi-3 showed that the amount of phloem parenchyma containing wall ingrowths was reduced 15-fold compared with wild-type. Discrete papillate wall ingrowths were formed in gi-2 plants but failed to develop into branched networks. Wall ingrowth development in gi-2 was not rescued by exposing these plants to high-light or cold conditions. In contrast, over-expression of GI in the gi-2 background restored wall ingrowth deposition to wild-type levels. These results indicate that GI regulates the ongoing development of wall ingrowth networks at a point downstream of inputs from environmental signals. [source] Arabidopsis Bax inhibitor-1 functions as an attenuator of biotic and abiotic types of cell deathTHE PLANT JOURNAL, Issue 6 2006Naohide Watanabe Summary Programmed cell death (PCD) is a common process in eukaryotes during development and in response to pathogens and stress signals. Bax inihibitor-1 (BI-1) is proposed to be a cell death suppressor that is conserved in both animals and plants, but the physiological importance of BI-1 and the impact of its loss of function in plants are still unclear. In this study, we identified and characterized two independent Arabidopsis mutants with a T-DNA insertion in the AtBI1 gene. The phenotype of atbi1-1 and atbi1-2, with a C-terminal missense mutation and a gene knockout, respectively, was indistinguishable from wild-type plants under normal growth conditions. However, these two mutants exhibit accelerated progression of cell death upon infiltration of leaf tissues with a PCD-inducing fungal toxin fumonisin B1 (FB1) and increased sensitivity to heat shock-induced cell death. Under these conditions, expression of AtBI1 mRNA was up-regulated in wild-type leaves prior to the activation of cell death, suggesting that increase of AtBI1 expression is important for basal suppression of cell death progression. Over-expression of AtBI1 transgene in the two homozygous mutant backgrounds rescued the accelerated cell death phenotypes. Together, our results provide direct genetic evidence for a role of BI-1 as an attenuator for cell death progression triggered by both biotic and abiotic types of cell death signals in Arabidopsis. [source] Formation of plant cuticle: evidence for the occurrence of the peroxygenase pathwayTHE PLANT JOURNAL, Issue 2 2003José Lequeu Summary Cuticle plays a major role as a protective barrier in plants. Despite its physiological importance, the mode of formation of this complex structure remains poorly understood. In particular, none of the putative enzymes involved in the biosynthesis of the cutin, the matrix of cuticle, have been cloned. We have shown previously that peroxygenase is able to catalyze in vitro the epoxidation step required for the biosynthesis of C18 cutin monomers. In the present work, we have confirmed in planta that this oxidase is indeed a key enzyme involved in the formation of cutin. Thus, in maize leaves, the specific inactivation of peroxygenase by organophosphorothioates resulted in a dramatic decrease of cuticular epoxide content, as visualized by a specific histochemical technique that was accompanied by a reduced thickness of the cuticle. A strict correlation could also be established between the extent of inhibition of the peroxygenase and the modification of the cuticle triggered by a family of structurally related inhibitors. Importantly, these effects were restricted to plants that contain a cutin originating from C18 monomers. The altered cuticle of maize, treated with the peroxygenase inhibitor, was characterized by an increased permeability to pesticides. In addition, such plants became largely susceptible to infection by fungi, implying that the cuticle represents a crucial target for the modulation of the response in plant,pathogen interactions. [source] Review of Hemoglobin-Vesicles as Artificial Oxygen CarriersARTIFICIAL ORGANS, Issue 2 2009Hiromi Sakai Abstract Blood transfusion systems have greatly benefited human health and welfare. Nevertheless, some problems remain: infection, blood type mismatching, immunological response, short shelf life, and screening test costs. Blood substitutes have been under development for decades to overcome such problems. Plasma component substitutes have already been established: plasma expanders, electrolytes, and recombinant coagulant factors. Herein, we focus on the development of red blood cell (RBC) substitutes. Side effects hindered early development of cell-free hemoglobin (Hb)-based oxygen carriers (HBOCs) and underscored the physiological importance of the cellular structure of RBCs. Well-designed artificial oxygen carriers that meet requisite criteria are expected to be realized eventually. Encapsulation of Hb is one idea to shield the toxicities of molecular Hbs. However, intrinsic issues of encapsulated Hbs must be resolved: difficulties related to regulating the molecular assembly, and management of its physicochemical and biochemical properties. Hb-vesicles (HbV) are a cellular type of HBOC that overcome these issues. The in vivo safety and efficacy of HbV have been studied extensively. The results illustrate the potential of HbV as a transfusion alternative and promise its use for other clinical applications that remain unattainable using RBC transfusion. [source] Expression, purification, crystallization and preliminary X-ray analysis of calmodulin in complex with the regulatory domain of the plasma-membrane Ca2+ -ATPase ACA8ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2010Henning Tidow Plasma-membrane Ca2+ -ATPases (PMCAs) are calcium pumps that expel Ca2+ from eukaryotic cells to maintain overall Ca2+ homoeostasis and to provide local control of intracellular Ca2+ signalling. They are of major physiological importance, with different isoforms being essential, for example, for presynaptic and postsynaptic Ca2+ regulation in neurons, feedback signalling in the heart and sperm motility. In the resting state, PMCAs are autoinhibited by binding of their C-terminal (in mammals) or N-terminal (in plants) tail to two major intracellular loops. Activation requires the binding of calcium-bound calmodulin (Ca2+ -CaM) to this tail and a conformational change that displaces the autoinhibitory tail from the catalytic domain. The complex between calmodulin and the regulatory domain of the plasma-membrane Ca2+ -ATPase ACA8 from Arabidopsis thaliana has been crystallized. The crystals belonged to space group C2, with unit-cell parameters a = 176.8, b = 70.0, c = 69.8,Å, , = 113.2°. A complete data set was collected to 3.0,Å resolution and structure determination is in progress in order to elucidate the mechanism of PMCA activation by calmodulin. [source] Transcriptional and translational control of C/EBPs: The case for "deep" genetics to understand physiological functionBIOESSAYS, Issue 8 2010Claus Nerlov Abstract The complexity of organisms is not simply determined by the number of their genes, but to a large extent by how gene expression is controlled. In addition to transcriptional regulation, this involves several layers of post-transcriptional control, such as translational repression, microRNA-mediated mRNA degradation and translational inhibition, alternative splicing, and the regulated generation of functionally distinct gene products from a single mRNA through alternative use of translation initiation sites. Much progress has been made in describing the molecular basis for these gene regulatory mechanisms. However, it is now a major challenge to translate this knowledge into deeper understanding of the physiological processes, both normal and pathological, that they govern. Using the C/EBP family of transcription factors as an example, the present review describes recent genetic experiments addressing this general problem and discusses how the physiological importance of newly discovered regulatory mechanisms might be determined. [source] Do studies in caveolin-knockouts teach us about physiology and pharmacology or instead, the ways mice compensate for ,lost proteins'?BRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2007P A Insel A wide array of phenotypic changes have been reported in mice with knockout of expression of caveolin-1. Neidhold et al. (2007) describe results in this issue that continue this trend by showing that saphenous arteries from adult caveolin-1 knockout mice lack caveolae, lose ,1 -adrenoceptor-promoted relaxation, gain ,3 -adrenoceptor-promoted relaxation but show no change in vasomotor response to ,2 -adrenoceptor activation. Neither the physiological importance for wild-type animals nor the mechanistic basis for these changes is clear. Although the caveolin-1 knockout and wild-type mice express similar levels of the receptor mRNAs, the protein expression of the receptors is not specified and represents, in our view, an important limitation of the study. We also question the physiological relevance of the findings and ask: Do studies in total body/lifespan caveolin-knockout mice further understanding of physiology and pharmacology or do they primarily characterize secondary consequences? We propose that alternative approaches that decrease caveolin expression in a temporally and spatially discrete manner are more likely to facilitate definitive conclusions regarding caveolin-1 and its role in regulation of , -adrenoceptors and other pharmacological targets. British Journal of Pharmacology (2007) 150, 251,254. doi:10.1038/sj.bjp.0706981 [source] | |||||||||||||