-
Molecules (Basel, Switzerland) Nov 2018Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast... (Review)
Review
Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast cancer resistance protein (BCRP/ABCG2), peptide transporters (PEPTs/SLC15), proton-coupled folate transporters (PCFT/SLC46A1), organic anion transporting polypeptides (OATPs/SLCO), organic anion transporters (OATs/SLC22), organic cation transporters (OCTs/SLC22), and multidrug and toxin extrusions (MATEs/SLC47) have been isolated, and their functions have been elucidated. Enantioselectivity has been demonstrated in the pharmacokinetics and efficacy of drugs, and is important for elucidating the relationship with recognition of drugs by drug transporters from a chiral aspect. Enantioselectivity in the transport of drugs by drug transporters and the inhibitory effects of drugs on drug transporters has been summarized in this review.
Topics: Animals; Humans; Membrane Transport Proteins; Molecular Structure; Pharmaceutical Preparations; Pharmacokinetics; Stereoisomerism; Structure-Activity Relationship; Tissue Distribution
PubMed: 30467304
DOI: 10.3390/molecules23123062 -
Trends in Plant Science Jun 2017Cytokinins are phytohormones essential for cytokinesis and many other physiological and developmental processes in planta. Long-distance transport and intercellular... (Review)
Review
Cytokinins are phytohormones essential for cytokinesis and many other physiological and developmental processes in planta. Long-distance transport and intercellular transport have been postulated. For these processes, the existence of cytokinin transporters has been suggested. Recently, a transporter loading the xylem (AtABCG14) and another for cellular import (AtPUP14) have been discovered. AtABCG14 participates in the xylem loading process of cytokinins and contributes to the positive regulation of shoot growth. The cellular importer AtPUP14 is required to suppress cytokinin signaling. A role of a transporter as stop signal is a new paradigm for a hormone transporter.
Topics: Arabidopsis; Arabidopsis Proteins; Biological Transport; Cytokinins; Membrane Transport Proteins; Signal Transduction
PubMed: 28372884
DOI: 10.1016/j.tplants.2017.03.003 -
Biomolecules Nov 2019Plastids, organelles that evolved from cyanobacteria via endosymbiosis in eukaryotes, provide carbohydrates for the formation of biomass and for mitochondrial energy... (Review)
Review
Plastids, organelles that evolved from cyanobacteria via endosymbiosis in eukaryotes, provide carbohydrates for the formation of biomass and for mitochondrial energy production to the cell. They generate their own energy in the form of the nucleotide adenosine triphosphate (ATP). However, plastids of non-photosynthetic tissues, or during the dark, depend on external supply of ATP. A dedicated antiporter that exchanges ATP against adenosine diphosphate (ADP) plus inorganic phosphate (Pi) takes over this function in most photosynthetic eukaryotes. Additional forms of such nucleotide transporters (NTTs), with deviating activities, are found in intracellular bacteria, and, surprisingly, also in diatoms, a group of algae that acquired their plastids from other eukaryotes via one (or even several) additional endosymbioses compared to algae with primary plastids and higher plants. In this review, we summarize what is known about the nucleotide synthesis and transport pathways in diatom cells, and discuss the evolutionary implications of the presence of the additional NTTs in diatoms, as well as their applications in biotechnology.
Topics: Biological Evolution; Biological Transport; Biotechnology; Diatoms; Membrane Transport Proteins; Nucleotides
PubMed: 31766535
DOI: 10.3390/biom9120761 -
Research in Microbiology 2018The over-expression of multidrug efflux pumps belonging to the Resistance-Nodulation-Division (RND) superfamily is one of the main causes of multidrug-resistance (MDR)... (Review)
Review
The over-expression of multidrug efflux pumps belonging to the Resistance-Nodulation-Division (RND) superfamily is one of the main causes of multidrug-resistance (MDR) in Gram-negative pathogenic bacteria. AcrB is the most thoroughly studied RND transporter and has functioned as a model for our understanding of efflux-mediated MDR. This multidrug-exporter can recognize and transport a wide range of structurally unrelated compounds (including antibiotics, dyes, bile salts and detergents), while it shows a strict inhibitor specificity. Here we discuss our current knowledge of AcrB, and include recent advances, regarding its structure, mechanism of drug transport, substrate recognition, different intramolecular entry pathways and the drug export driven by remote conformational coupling.
Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Biological Transport; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Membrane Transport Proteins
PubMed: 29807096
DOI: 10.1016/j.resmic.2018.05.005 -
The Biochemical Journal Feb 2017Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both... (Review)
Review
Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.
Topics: ATP-Binding Cassette Transporters; Alzheimer Disease; Animals; Astrocytes; GABA Plasma Membrane Transport Proteins; Gene Expression Regulation; Glucose Transport Proteins, Facilitative; Glutamate Plasma Membrane Transport Proteins; Glycine Plasma Membrane Transport Proteins; Humans; Membrane Transport Proteins; Multigene Family; Serotonin Plasma Membrane Transport Proteins; Signal Transduction; Sodium-Potassium-Exchanging ATPase
PubMed: 28108584
DOI: 10.1042/BCJ20160505 -
Nature Communications May 2023The kidney plays a key role in the correction of systemic acid-base imbalances. Central for this regulation are the intercalated cells in the distal nephron, which...
The kidney plays a key role in the correction of systemic acid-base imbalances. Central for this regulation are the intercalated cells in the distal nephron, which secrete acid or base into the urine. How these cells sense acid-base disturbances is a long-standing question. Intercalated cells exclusively express the Na-dependent Cl/HCO exchanger AE4 (Slc4a9). Here we show that AE4-deficient mice exhibit a major dysregulation of acid-base balance. By combining molecular, imaging, biochemical and integrative approaches, we demonstrate that AE4-deficient mice are unable to sense and appropriately correct metabolic alkalosis and acidosis. Mechanistically, a lack of adaptive base secretion via the Cl/HCO exchanger pendrin (Slc26a4) is the key cellular cause of this derailment. Our findings identify AE4 as an essential part of the renal sensing mechanism for changes in acid-base status.
Topics: Mice; Animals; Kidney; Membrane Transport Proteins; Acid-Base Equilibrium; Nephrons; Sulfate Transporters; Bicarbonates; Chloride-Bicarbonate Antiporters
PubMed: 37236964
DOI: 10.1038/s41467-023-38562-x -
ELife Jun 2018A simple label-free method uses the electrical properties of cells to detect how ligands bind to membrane proteins.
A simple label-free method uses the electrical properties of cells to detect how ligands bind to membrane proteins.
Topics: Biophysical Phenomena; Ligands; Membrane Glycoproteins; Membrane Proteins; Membrane Transport Proteins; Serotonin Plasma Membrane Transport Proteins
PubMed: 29877799
DOI: 10.7554/eLife.37910 -
Nature Reviews. Drug Discovery Jan 2015Potential drug-drug interactions mediated by the ATP-binding cassette (ABC) transporter and solute carrier (SLC) transporter families are of clinical and regulatory... (Review)
Review
Potential drug-drug interactions mediated by the ATP-binding cassette (ABC) transporter and solute carrier (SLC) transporter families are of clinical and regulatory concern. However, the endogenous functions of these drug transporters are not well understood. Discussed here is evidence for the roles of ABC and SLC transporters in the handling of diverse substrates, including metabolites, antioxidants, signalling molecules, hormones, nutrients and neurotransmitters. It is suggested that these transporters may be part of a larger system of remote communication ('remote sensing and signalling') between cells, organs, body fluid compartments and perhaps even separate organisms. This broader view may help to clarify disease mechanisms, drug-metabolite interactions and drug effects relevant to diabetes, chronic kidney disease, metabolic syndrome, hypertension, gout, liver disease, neuropsychiatric disorders, inflammatory syndromes and organ injury, as well as prenatal and postnatal development.
Topics: ATP-Binding Cassette Transporters; Animals; Biological Transport; Drug Interactions; Humans; Membrane Transport Proteins; Organic Anion Transporters; Pharmaceutical Preparations
PubMed: 25475361
DOI: 10.1038/nrd4461 -
Advances in Neurobiology 2023Monoamine transporters (MATs) are targets of a wide range of compounds that have been developed as therapeutic treatments for various neuropsychiatric and... (Review)
Review
Monoamine transporters (MATs) are targets of a wide range of compounds that have been developed as therapeutic treatments for various neuropsychiatric and neurodegenerative disorders such as depression, ADHD, neuropathic pain, anxiety disorders, stimulant use disorders, epilepsy, and Parkinson's disease. The MAT family is comprised of three main members - the dopamine transporter (DAT), the norepinephrine transporter (NET), and the serotonin transporter (SERT). These transporters are through reuptake responsible for the clearance of their respective monoamine substrates from the extracellular space. The determination of X-ray crystal structures of MATs and their homologues bound with various substrates and ligands has resulted in a surge of structure-function-based studies of MATs to understand the molecular basis of transport function and the mechanism of various ligands that ultimately result in their behavioral effects. This review focusses on recent examples of ligand-based structure-activity relationship studies trying to overcome some of the challenges associated with previously developed MAT inhibitors. These studies have led to the discovery of unique and novel structurally diverse MAT ligands including allosteric modulators. These novel molecular scaffolds serve as leads for designing more effective therapeutic interventions by modulating the activities of MATs and ultimately their associated neurotransmission and behavioral effects.
Topics: Humans; Biological Transport; Ligands; Serotonin Plasma Membrane Transport Proteins; Vesicular Monoamine Transport Proteins; Mental Disorders; Drug Discovery
PubMed: 36928847
DOI: 10.1007/978-3-031-21054-9_4 -
Disease Models & Mechanisms Nov 2023By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic... (Review)
Review
By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.
Topics: Humans; Membrane Transport Proteins; Solute Carrier Proteins; Biological Transport; Neoplasms; Cell Physiological Phenomena; Tumor Microenvironment
PubMed: 38037877
DOI: 10.1242/dmm.050404