transporter function
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INTRODUCTION: Medication of pregnant women is increasingly common in developed countries. Several placental drug transporters have been shown to transfer their substrates from the trophoblast back to the maternal circulation, thus hindering the transplacental passage of xenobiotics and protecting the fetus. However, the expression and activity of drug transporter proteins in the placenta vary during gestation and are tightly regulated by many factors. In addition, their function can be compromised by pathological conditions and/or drug-drug interactions. AREAS COVERED: This article reviews current knowledge on placental drug transporters, their effects on placental pharmacokinetics and the regulatory mechanisms that control their expression and activity. Transcriptional, genetic and epigenetic mechanisms of placental transporter regulation and the drug-drug interactions that modulate transporter activity are described. Physiological and pathological factors that can affect drug transporter expression and function in the placenta are also discussed. EXPERT OPINION: The expression and activity of drug transporter proteins in the placenta vary during gestation and are tightly regulated by many factors. Subsequently, there is a great variability in the expression and function of placental drug transporters both within human populations (interindividual variability) and also during gestation (intraindividual variability). An understanding of the expression and function of placental drug transporters is essential for efficient and safe therapy during pregnancy. There is clearly a need for further preclinical and clinical studies on placental drug transporters, but such investigations must be carefully designed and the resulting data should be evaluated with great caution. This review highlights several methodological aspects that will have to be considered and addressed in order to shed further light on these important issues.
- MeSH
- biologický transport fyziologie MeSH
- lékové interakce MeSH
- lidé MeSH
- maternofetální výměna látek fyziologie MeSH
- membránové transportní proteiny genetika metabolismus MeSH
- placenta metabolismus MeSH
- těhotenství MeSH
- xenobiotika škodlivé účinky farmakokinetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Brassinosteroids are steroidal phytohormones that regulate plant development and physiology, including adaptation to environmental stresses. Brassinosteroids are synthesized in the cell interior but bind receptors at the cell surface, necessitating a yet to be identified export mechanism. Here, we show that a member of the ATP-binding cassette (ABC) transporter superfamily, ABCB19, functions as a brassinosteroid exporter. We present its structure in both the substrate-unbound and the brassinosteroid-bound states. Bioactive brassinosteroids are potent activators of ABCB19 ATP hydrolysis activity, and transport assays showed that ABCB19 transports brassinosteroids. In Arabidopsis thaliana, ABCB19 and its close homolog, ABCB1, positively regulate brassinosteroid responses. Our results uncover an elusive export mechanism for bioactive brassinosteroids that is tightly coordinated with brassinosteroid signaling.
- MeSH
- ABC transportéry * chemie genetika metabolismus MeSH
- adenosintrifosfát metabolismus MeSH
- Arabidopsis * genetika metabolismus MeSH
- brassinosteroidy * metabolismus MeSH
- konformace proteinů MeSH
- kyseliny indoloctové metabolismus MeSH
- proteiny huseníčku * chemie genetika metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
Alzheimer's disease (AD) is a devastating neurological disorder characterized by the pathological accumulation of macromolecular Aβ and tau leading to neuronal death. Drugs approved to treat AD may ameliorate disease symptoms, however, no curative treatment exists. Aβ peptides were discovered to be substrates of adenosine triphosphate-(ATP)-binding cassette (ABC) transporters. Activators of these membrane-bound efflux proteins that promote binding and/or translocation of Aβ could revolutionize AD medicine. The knowledge about ABC transporter activators is very scarce, however, the few molecules that were reported contain substructural features of multitarget (pan-)ABC transporter inhibitors. A cutting-edge strategy to obtain new drug candidates is to explore and potentially exploit the recently proposed multitarget binding site of pan-ABC transporter inhibitors as anchor point for the development of innovative activators to promote Aβ clearance from the brain. Molecular associations between functional bioactivities and physicochemical properties of small-molecules are key to understand these processes. This study provides an analysis of a recently reported unique multitarget dataset for the correlation between multitarget bioactivity and physicochemistry. Six novel pan-ABC transporter inhibitors were validated containing substructural features of ABC transporter activators, which underpins the relevance of the multitarget binding site for the targeted development of novel AD diagnostics and therapeutics.
BACKGROUND: The ATP-binding cassette (ABC) transporter superfamily is comprised predominantly of proteins which directly utilize energy from ATP to move molecules across the plasma membrane. Although they have been the subject of frequent investigation across many taxa, arthropod ABCs have been less well studied. While the manual annotation of ABC transporters has been performed in many arthropods, there has so far been no systematic comparison of the superfamily within this order using the increasing number of sequenced genomes. Furthermore, functional work on these genes is limited. RESULTS: Here, we developed a standardized pipeline to annotate ABCs from predicted proteomes and used it to perform comparative genomics on ABC families across arthropod lineages. Using Kruskal-Wallis tests and the Computational Analysis of gene Family Evolution (CAFE), we were able to observe significant expansions of the ABC-B full transporters (P-glycoproteins) in Lepidoptera and the ABC-H transporters in Hemiptera. RNA-sequencing of epithelia tissues in the Lepidoptera Helicoverpa armigera showed that the 7 P-glycoprotein paralogues differ substantially in their tissue distribution, suggesting a spatial division of labor. It also seems that functional redundancy is a feature of these transporters as RNAi knockdown showed that most transporters are dispensable with the exception of the highly conserved gene Snu, which is probably due to its role in cuticular formation. CONCLUSIONS: We have performed an annotation of the ABC superfamily across > 150 arthropod species for which good quality protein annotations exist. Our findings highlight specific expansions of ABC transporter families which suggest evolutionary adaptation. Future work will be able to use this analysis as a resource to provide a better understanding of the ABC superfamily in arthropods.
The shaping of organs in plants depends on the intercellular flow of the phytohormone auxin, of which the directional signaling is determined by the polar subcellular localization of PIN-FORMED (PIN) auxin transport proteins. Phosphorylation dynamics of PIN proteins are affected by the protein phosphatase 2A (PP2A) and the PINOID kinase, which act antagonistically to mediate their apical-basal polar delivery. Here, we identified the ROTUNDA3 (RON3) protein as a regulator of the PP2A phosphatase activity in Arabidopsis thaliana. The RON3 gene was map-based cloned starting from the ron3-1 leaf mutant and found to be a unique, plant-specific gene coding for a protein with high and dispersed proline content. The ron3-1 and ron3-2 mutant phenotypes [i.e., reduced apical dominance, primary root length, lateral root emergence, and growth; increased ectopic stages II, IV, and V lateral root primordia; decreased auxin maxima in indole-3-acetic acid (IAA)-treated root apical meristems; hypergravitropic root growth and response; increased IAA levels in shoot apices; and reduced auxin accumulation in root meristems] support a role for RON3 in auxin biology. The affinity-purified PP2A complex with RON3 as bait suggested that RON3 might act in PIN transporter trafficking. Indeed, pharmacological interference with vesicle trafficking processes revealed that single ron3-2 and double ron3-2 rcn1 mutants have altered PIN polarity and endocytosis in specific cells. Our data indicate that RON3 contributes to auxin-mediated development by playing a role in PIN recycling and polarity establishment through regulation of the PP2A complex activity.
- MeSH
- Arabidopsis genetika růst a vývoj metabolismus MeSH
- biologické modely MeSH
- geneticky modifikované rostliny MeSH
- hybridizace in situ MeSH
- konfokální mikroskopie MeSH
- kořeny rostlin genetika růst a vývoj metabolismus MeSH
- kyseliny indoloctové metabolismus MeSH
- listy rostlin genetika růst a vývoj metabolismus MeSH
- membránové transportní proteiny genetika metabolismus MeSH
- mutace MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- proteinfosfatasa 2 metabolismus MeSH
- proteiny huseníčku genetika metabolismus MeSH
- regulace genové exprese u rostlin MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Předpokládá se, že kognitivní funkce mohou být v genetických studiích u psychiatrických poruch vhodnějším fenotypem než samotný klinický obraz, který je více ovlivněn faktory prostředí (Gottesman, 2003). U ADHD je přítomna porucha kognitivních funkcí z definice této poruchy. Od nehyperkinetické populace se skupina pacientů s ADHD odlišuje poruchou pozornosti a zvýšenou impulzivitou. Další poruchy existují v inhibici motoriky. Bylo zjištěno, že chybná inhibice odpovědi (která souvisí s impulzivitou) je vhodným endofenotypem ADHD a vyskytuje se i u příbuzných pacientů, kteří nevykazují klinické známky ADHD (Slaats-Willemse, 2003, Aron 2005). Vhodným endofenotypem je rovněž pozornost (Fan, 2001). Metodika: V naší práci jsme zkoumali korelace mezi genotypem a výsledky neuropsychologických testů (TDT, TE-NA-ZO a baterie NES2) u homogenní kavkazské populace 119 chlapců ve věku 7-13 let s dg. hyperkinetická porucha (F90.X dle MKN-10) - dále HKP. Byl stanoven genotyp pro "dopaminové" geny (DRD2, DRD4, DAT). Výsledky: V souboru jsme hledali korelaci mezi výsledky psychologických testů a genotypy jednotlivých genů. Korelační koeficienty pro žádnou kombinaci nebyly statisticky signifikantně odlišné od náhodného rozdělení. Závěr: V našem souboru jsme neprokázali korelace mezi polymorfismy "dopaminových" genů a výsledky neuropsychologických testů. Polymorfismus těchto genů v populaci českých hypekinetických chlapců neovlivňuje výkony v psychologických testech.
It is assumed that cognitive functions may be a better phenotype in genetic studies of psychiatric disorders than clinical picture itself as it is more influenced by the external factors (Gottesman, 2003). A cognitive deficit is present in ADHD patients as a matter of definition. The ADHD group differs from the non-ADHD population in terms of attention deficit and increased impulsivity. Other deficits exist in motor function inhibition. It has been found that incorrect response inhibition (which relates to impulsivity) is a suitable endophenotype of ADHD and is present as well in relatives of patients who themselves do not express clinical signs od ADHD (Slaats-Willemse, 2003, Aron, 2005). Attention is a suitable endophenotype as well (Fan, 2001). Method: In the present study the correlations between genotype and results of neuropsychological tests (TDT, TE-NA-ZO and NES2 battery) were studied in a homogenous Caucasian population of 119 boys in the age range 7-13 diagnosed with Hyperkinetic disorder (HKP - F90.X according to the ICD-10). The genotype for "dopaminergic" genes (DRD2, DRD4, DAT) was assessed. Results: Correlations between the results of psychological tests and genotypes of each gene were examined. The correlation coeficients for any combination were not significantly different from a random distribution. Conclusion: We did not prove any correlations between the "dopaminergic" genes polymorphisms and the results of neuropsychological tests in our sample. Polymorphisms of these genes do not influence the performance in psychological tests in the population of Czech hyperkinetic boys.
The human dopamine transporter gene SLC6A3 has been consistently implicated in several neuropsychiatric diseases but the disease mechanism remains elusive. In this risk synthesis, we have concluded that SLC6A3 represents an increasingly recognized risk with a growing number of familial mutants associated with neuropsychiatric and neurological disorders. At least five loci were related to common and severe diseases including alcohol use disorder (high activity variant), attention-deficit/hyperactivity disorder (low activity variant), autism (familial proteins with mutated networking) and movement disorders (both regulatory variants and familial mutations). Association signals depended on genetic markers used as well as ethnicity examined. Strong haplotype selection and gene-wide epistases support multimarker assessment of functional variations and phenotype associations. Inclusion of its promoter region's functional markers such as DNPi (rs67175440) and 5'VNTR (rs70957367) may help delineate condensate-based risk action, testing a locus-pathway-phenotype hypothesis for one gene-multidisease etiology.
The phosphate transporter PHT4;6 locates to the trans-Golgi compartment, and its impaired activity causes altered intracellular phosphate compartmentation, leading to low cytosolic Pi levels, a blockage of Golgi-related processes such as protein glycosylation and hemicellulose biosynthesis, and a dwarf phenotype. However, it was unclear whether altered Pi homeostasis in pht4;6 mutants causes further cellular problems, typically associated with limited phosphate availability. Here we report that pht4;6 mutants exhibit a markedly increased disposition to induce dark-induced senescence. In control experiments, in which pht4;6 mutants and wild-type plants developed similarly, we confirmed that accelerated dark-induced senescence in mutants is not a 'pleiotropic' process associated with the dwarf phenotype. In fact, accelerated dark-induced senescence in pht4;6 mutants correlates strongly with increased levels of toxic NH4 (+) and higher sensitivity to ammonium, which probably contribute to the inability of pht4;6 mutants to recover from dark treatment. Experiments with modified levels of either salicylic acid (SA) or trans-zeatin (tZ) demonstrate that altered concentrations of these compounds in pht4;6 plants act as major cellular mediators for dark-induced senescence. This conclusion gained further support from the notion that the expression of the pht4;6 gene is, in contrast to genes coding for major phosphate importers, substantially induced by tZ. Taken together, our findings point to a critical function of PHT4;6 to control cellular phosphate levels, in particular the cytosolic Pi availability, required to energize plant primary metabolism for proper plant development. Phosphate and its allocation mediated by PHT4;6 is critical to prevent onset of dark-induced senescence.
- MeSH
- Arabidopsis metabolismus fyziologie MeSH
- chlorofyl metabolismus MeSH
- cytokininy metabolismus MeSH
- Golgiho aparát metabolismus fyziologie MeSH
- proteiny huseníčku fyziologie MeSH
- proteiny přenášející fosfát fyziologie MeSH
- regulace genové exprese u rostlin fyziologie MeSH
- stárnutí fyziologie MeSH
- světlo MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- ABC transportéry farmakokinetika MeSH
- finanční podpora výzkumu jako téma MeSH
- játra enzymologie fyziologie sekrece MeSH
- lidé MeSH
- mnohočetná léková rezistence fyziologie genetika imunologie MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům farmakokinetika fyziologie genetika MeSH
- transportní proteiny farmakokinetika MeSH
- xenobiotika farmakokinetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
