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Physiological Reviews Jul 2013Glucose is an important fuel for contracting muscle, and normal glucose metabolism is vital for health. Glucose enters the muscle cell via facilitated diffusion through... (Review)
Review
Glucose is an important fuel for contracting muscle, and normal glucose metabolism is vital for health. Glucose enters the muscle cell via facilitated diffusion through the GLUT4 glucose transporter which translocates from intracellular storage depots to the plasma membrane and T-tubules upon muscle contraction. Here we discuss the current understanding of how exercise-induced muscle glucose uptake is regulated. We briefly discuss the role of glucose supply and metabolism and concentrate on GLUT4 translocation and the molecular signaling that sets this in motion during muscle contractions. Contraction-induced molecular signaling is complex and involves a variety of signaling molecules including AMPK, Ca(2+), and NOS in the proximal part of the signaling cascade as well as GTPases, Rab, and SNARE proteins and cytoskeletal components in the distal part. While acute regulation of muscle glucose uptake relies on GLUT4 translocation, glucose uptake also depends on muscle GLUT4 expression which is increased following exercise. AMPK and CaMKII are key signaling kinases that appear to regulate GLUT4 expression via the HDAC4/5-MEF2 axis and MEF2-GEF interactions resulting in nuclear export of HDAC4/5 in turn leading to histone hyperacetylation on the GLUT4 promoter and increased GLUT4 transcription. Exercise training is the most potent stimulus to increase skeletal muscle GLUT4 expression, an effect that may partly contribute to improved insulin action and glucose disposal and enhanced muscle glycogen storage following exercise training in health and disease.
Topics: Biological Transport; Exercise; Glucose; Glucose Transporter Type 4; Humans; Muscle, Skeletal; Sarcolemma
PubMed: 23899560
DOI: 10.1152/physrev.00038.2012 -
Nature Cell Biology Jun 2022Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied...
Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied forces. Such forces can lead to the nuclear translocation of proteins, but whether force controls nucleocytoplasmic transport, and how, remains unknown. Here we show that nuclear forces differentially control passive and facilitated nucleocytoplasmic transport, setting the rules for the mechanosensitivity of shuttling proteins. We demonstrate that nuclear force increases permeability across nuclear pore complexes, with a dependence on molecular weight that is stronger for passive than for facilitated diffusion. Owing to this differential effect, force leads to the translocation of cargoes into or out of the nucleus within a given range of molecular weight and affinity for nuclear transport receptors. Further, we show that the mechanosensitivity of several transcriptional regulators can be both explained by this mechanism and engineered exogenously by introducing appropriate nuclear localization signals. Our work unveils a mechanism of mechanically induced signalling, probably operating in parallel with others, with potential applicability across signalling pathways.
Topics: Active Transport, Cell Nucleus; Cell Nucleus; Nuclear Pore; Protein Transport; Receptors, Cytoplasmic and Nuclear
PubMed: 35681009
DOI: 10.1038/s41556-022-00927-7 -
Cells Oct 2019Aquaporins are integral membrane proteins that facilitate the diffusion of water and other small, uncharged solutes across the cellular membrane and are widely... (Review)
Review
Aquaporins are integral membrane proteins that facilitate the diffusion of water and other small, uncharged solutes across the cellular membrane and are widely distributed in organisms from humans to bacteria. However, the characteristics of prokaryotic aquaporins remain largely unknown. We investigated the distribution and sequence characterization of aquaporins in prokaryotic organisms and summarized the transport characteristics, physiological functions, and regulatory mechanisms of prokaryotic aquaporins. Aquaporin homologues were identified in 3315 prokaryotic genomes retrieved from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, but the protein clustering pattern is not completely congruent with the phylogeny of the species that carry them. Moreover, prokaryotic aquaporins display diversified aromatic/arginine constriction region (ar/R) amino acid compositions, implying multiple functions. The typical water and glycerol transport characterization, physiological functions, and regulations have been extensively studied in AqpZ and GlpF. A aquaporin has recently been verified to facilitate the efflux of endogenous HO, which not only contributes to detoxification but also to species competitiveness, improving our understanding of prokaryotic aquaporins. Furthermore, recent studies revealed novel regulatory mechanisms of prokaryotic aquaporins at post-translational level. Thus, we propose that intensive investigation on prokaryotic aquaporins would extend the functional categories and working mechanisms of these ubiquitous, intrinsic membrane proteins.
Topics: Amino Acid Sequence; Aquaporins; Biological Transport; Escherichia coli; Escherichia coli Proteins; Hydrogen Peroxide; Membrane Proteins; Phylogeny; Prokaryotic Cells; Water
PubMed: 31653102
DOI: 10.3390/cells8111316 -
Biophysical Reviews Dec 2017It is, nowadays, possible to simulate biological processes in conditions that mimic the different cellular compartments. Several groups have performed these calculations... (Review)
Review
It is, nowadays, possible to simulate biological processes in conditions that mimic the different cellular compartments. Several groups have performed these calculations using molecular models that vary in performance and accuracy. In many cases, the atomistic degrees of freedom have been eliminated, sacrificing both structural complexity and chemical specificity to be able to explore slow processes. In this review, we will discuss the insights gained from computer simulations on macromolecule diffusion, nuclear body formation, and processes involving the genetic material inside cell-mimicking spaces. We will also discuss the challenges to generate new models suitable for the simulations of biological processes on a cell scale and for cell-cycle-long times, including non-equilibrium events such as the co-translational folding, misfolding, and aggregation of proteins. A prominent role will be played by the wise choice of the structural simplifications and, simultaneously, of a relatively complex energetic description. These challenging tasks will rely on the integration of experimental and computational methods, achieved through the application of efficient algorithms. Graphical abstract.
PubMed: 29185136
DOI: 10.1007/s12551-017-0363-6 -
RNA Biology Sep 2019Argonaute (Ago) proteins are of key importance in many cellular processes. In eukaryotes, Ago can induce translational repression followed by deadenylation and... (Review)
Review
Argonaute (Ago) proteins are of key importance in many cellular processes. In eukaryotes, Ago can induce translational repression followed by deadenylation and degradation of mRNA molecules through base pairing of microRNAs (miRNAs) with a complementary target on a mRNA sequence. In bacteria, Ago eliminates foreign DNA through base pairing of siDNA (small interfering DNA) with a target on a DNA sequence. Effective targeting activities of Ago require fast recognition of the cognate target sequence among numerous off-target sites. Other target search proteins such as transcription factors (TFs) are known to rely on facilitated diffusion for this goal, but it is undetermined to what extent these small nucleic acid-guided proteins utilize this mechanism. Here, we review recent single-molecule studies on Ago target search. We discuss the consequences of the recent findings on the search mechanism. Furthermore, we discuss the open standing research questions that need to be addressed for a complete picture of facilitated target search by small nucleic acids.
Topics: Argonaute Proteins; Bacteria; Base Sequence; DNA; MicroRNAs; RNA, Messenger; Single Molecule Imaging; Transcription Factors
PubMed: 31068066
DOI: 10.1080/15476286.2019.1616353 -
Biophysical Reviews Mar 2016Glucose is a primary energy source for most cells and an important substrate for many biochemical reactions. As glucose is a need of each and every cell of the body, so... (Review)
Review
Glucose is a primary energy source for most cells and an important substrate for many biochemical reactions. As glucose is a need of each and every cell of the body, so are the glucose transporters. Consequently, all cells express these important proteins on their surface. In recent years developments in genetics have shed new light on the types and physiology of various glucose transporters, of which there are two main types-sodium-glucose linked transporters (SGLTs) and facilitated diffusion glucose transporters (GLUT)-which can be divided into many more subclasses. Transporters differ in terms of their substrate specificity, distribution and regulatory mechanisms. Glucose transporters have also received much attention as therapeutic targets for various diseases. In this review, we attempt to present a simplified view of this complex topic which may be of interest to researchers involved in biochemical and pharmacological research.
PubMed: 28510148
DOI: 10.1007/s12551-015-0186-2 -
Marine Drugs 2011Dietary carotenoids, especially xanthophylls, have attracted significant attention because of their characteristic biological activities, including anti-allergic,... (Review)
Review
Dietary carotenoids, especially xanthophylls, have attracted significant attention because of their characteristic biological activities, including anti-allergic, anti-cancer, and anti-obese actions. Although no less than forty carotenoids are ingested under usual dietary habits, only six carotenoids and their metabolites have been found in human tissues, suggesting selectivity in the intestinal absorption of carotenoids. Recently, facilitated diffusion in addition to simple diffusion has been reported to mediate the intestinal absorption of carotenoids in mammals. The selective absorption of carotenoids may be caused by uptake to the intestinal epithelia by the facilitated diffusion and an unknown excretion to intestinal lumen. It is well known that β-carotene can be metabolized to vitamin A after intestinal absorption of carotenoids, but little is known about the metabolic transformation of non provitamin A xanthophylls. The enzymatic oxidation of the secondary hydroxyl group leading to keto-carotenoids would occur as a common pathway of xanthophyll metabolism in mammals. This paper reviews the absorption and metabolism of xanthophylls by introducing recent advances in this field.
Topics: Animals; Diet; Facilitated Diffusion; Humans; Intestinal Absorption; Intestinal Mucosa; Xanthophylls
PubMed: 21747746
DOI: 10.3390/md9061024 -
FEBS Letters Aug 2016Various signaling pathways coordinate energy metabolism and contractile function in the heart. Myocardial uptake of long-chain fatty acids largely occurs by facilitated... (Review)
Review
Various signaling pathways coordinate energy metabolism and contractile function in the heart. Myocardial uptake of long-chain fatty acids largely occurs by facilitated diffusion, involving the membrane-associated protein, CD36. Glucose uptake, the rate-limiting step in glucose utilization, is mediated predominantly by the glucose transporter protein, GLUT4. Insulin and contraction-mediated AMPK signaling each are implicated in tightly regulating these myocardial 'gate-keepers' of energy balance, that is, CD36 and GLUT4. The insulin and AMPK signaling cascades are complex and their cross-talk is only beginning to be understood. Moreover, transcriptional regulation of the CD36 and GLUT4 is significantly understudied. This review focuses on recent advances on the role of these signaling pathways and transcription factors involved in the regulation of CD36 and GLUT4.
Topics: AMP-Activated Protein Kinases; CD36 Antigens; Energy Metabolism; Glucose; Glucose Transporter Type 4; Humans; Insulin; Myocardium; Signal Transduction
PubMed: 27403883
DOI: 10.1002/1873-3468.12297 -
Nucleic Acids Research May 2022How type 2 Topoisomerase (TopoII) proteins relax and simplify the topology of DNA molecules is one of the most intriguing open questions in genome and DNA biophysics....
How type 2 Topoisomerase (TopoII) proteins relax and simplify the topology of DNA molecules is one of the most intriguing open questions in genome and DNA biophysics. Most of the existing models neglect the dynamics of TopoII which is expected of proteins searching their targets via facilitated diffusion. Here, we show that dynamic binding of TopoII speeds up the topological relaxation of knotted substrates by enhancing the search of the knotted arc. Intriguingly, this in turn implies that the timescale of topological relaxation is virtually independent of the substrate length. We then discover that considering binding biases due to facilitated diffusion on looped substrates steers the sampling of the topological space closer to the boundaries between different topoisomers yielding an optimally fast topological relaxation. We discuss our findings in the context of topological simplification in vitro and in vivo.
Topics: DNA Topoisomerases, Type II; DNA; Isomerases; Genome
PubMed: 35474478
DOI: 10.1093/nar/gkac260