The cellular functions of clathrin

Membranes and proteins are moved around the cell in small vesicles. A protein coat aids the budding of such vesicles from donor membranes. The major type of coat used by the cell is composed of clathrin, a three-legged protein that can form lattice-like coats on membranes destined for trafficking. In this review, I outline what we know about clathrin and discuss some recent advances in understanding the basic biology of this fascinating molecule, which include building a molecular model of a clathrin lattice and discovery of a new function for clathrin that occurs during mitosis. Received 12 December 2005; received after revision 21 March 2006; accepted 29 March 2006     

Lipid flippases and their biological functions

The typically distinct phospholipid composition of the two leaflets of a membrane bilayer is generated and maintained by bi-directional transport (flip-flop) of lipids between the leaflets. Specific membrane proteins, termed lipid flippases, play an essential role in this transport process. Energy-independent flippases allow common phospholipids to equilibrate rapidly between the two monolayers and also play a role in the biosynthesis of a variety of glycoconjugates such as glycosphingolipids, N-glycoproteins, and glycosylphosphatidylinositol (GPI)-anchored proteins. ATP-dependent flippases, including members of a conserved subfamily of P-type ATPases and ATP-binding cassette transporters, mediate the net transfer of specific phospholipids to one leaflet of a membrane and are involved in the creation and maintenance of transbilayer lipid asymmetry of membranes such as the plasma membrane of eukaryotes. Energy-dependent flippases also play a role in the biosynthesis of glycoconjugates such as bacterial lipopolysaccharide. This review summarizes recent progress on the identification and characterization of the various flippases and the demonstration of their biological functions. Received 12 April 2006; received after revision 22 June 2006; accepted 30 August 2006     

Gelsolin superfamily proteins: key regulators of cellular functions

Cytoskeletal rearrangement occurs in a variety of cellular processes and involves a wide spectrum of proteins. Among these, the gelsolin superfamily proteins control actin organization by severing filaments, capping filament ends and nucleating actin assembly [1]. Gelsolin is the founding member of this family, which now contains at least another six members: villin, adseverin, capG, advillin, supervillin and flightless I. In addition to their respective role in actin filament remodeling, these proteins have some specific and apparently non-overlapping particular roles in several cellular processes, including cell motility, control of apoptosis and regulation of phagocytosis (summarized in table 1). Evidence suggests that proteins belonging to the gelsolin superfamily may be involved in other processes, including gene expression regulation. This review will focus on some of the known functions of the gelsolin superfamily proteins, thus providing a basis for reflection on other possible and as yet incompletely understood roles for these proteins.     

LOX-1 in atherosclerosis: biological functions and pharmacological modifiers

Lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1, also known as OLR-1), is a class E scavenger receptor that mediates the uptake of oxLDL by vascular cells. LOX-1 is involved in endothelial dysfunction, monocyte adhesion, the proliferation, migration, and apoptosis of smooth muscle cells, foam cell formation, platelet activation, as well as plaque instability; all of these events are critical in the pathogenesis of atherosclerosis. These LOX-1-dependent biological processes contribute to plaque instability and the ultimate clinical sequelae of plaque rupture and life-threatening tissue ischemia. Administration of anti-LOX-1 antibodies inhibits atherosclerosis by decreasing these cellular events. Over the past decade, multiple drugs including naturally occurring antioxidants, statins, antiinflammatory agents, antihypertensive and antihyperglycemic drugs have been demonstrated to inhibit vascular LOX-1 expression and activity. Therefore, LOX-1 represents an attractive therapeutic target for the treatment of human atherosclerotic diseases. This review aims to integrate the current understanding of LOX-1 signaling, regulation of LOX-1 by vasculoprotective drugs, and the importance of LOX-1 in the pathogenesis of atherosclerosis.     

Trypsin and trypsin-like proteases in the brain: Proteolysis and cellular functions

Several serine proteases including thrombin, tissue-type plasminogen activator and urokinase-type plasminogen activator have been well characterized in the brain. In this article, we review the brain-related trypsin and trypsin-like serine proteases. Accumulating evidence demonstrates that trypsin and trypsin-like serine proteases play very important roles in neural development, plasticity, neurodegeneration and neuroregeneration in the brain. Neuropsin is able to hydrolyze the extracellular matrix components by its active site serine, and regulates learning and memory in normal brain. The mutant neurotrypsin contributes to mental retardation in children. Neurosin seems to be involved in the pathogenesis of neurodegenerative disorders, like Alzheimer’s disease, Parkinson’s disease or multiple sclerosis. Although mesotrypsin/trypsin IV is also implicated in neurodegeneration, its functional significance still remains largely unknown. Particularly, mesotrypsin/trypsin IV, P22 and neurosin exert their physiological and pathological functions through activation of certain protease-activated receptors (PARs). In the brain, the presence of serpins controls the activity of serine proteases. Therefore, understanding the interaction among brain trypsin, serpins and PARs will provide invaluable tools for regulating normal brain functions and for the clinical treatment of neural disorders. Y. Wang, W. Luo: These authors made equal contributions. Received 26 June 2007; received after revision 13 August 2007; accepted 12 September 2007     

Effect of K and Mg aspartate on cellular metabolism

Zusammenfassung Gasstoffwechselbestimmungen von unter K- und Mg-Asparaginat stehenden Zellenpräparaten isolierter Nephronen zeigen vermehrten Sauerstoffverbrauch. Der dabei unveränderte Atmungskoeffizient beweist, dass das oxydierte Substrat offenbar dasselbe bleibt.     

Scaffolds,levers, rods and springs: diverse cellular functions of long coiled-coil proteins

Long alpha-helical coiled-coil proteins are involved in a variety of organizational and regulatory processes in eukaryotic cells. They provide cables and networks in the cyto- and nucleoskeleton, molecular scaffolds that organize membrane systems, motors, levers, rotating arms and possibly springs. A growing number of human diseases are found to be caused by mutations in long coiled-coil proteins. This review summarizes our current understanding of the multifaceted group of long coiled-coil proteins in the cytoskeleton, nucleus, Golgi and cell division apparatus. The biophysical features of coiled-coil domains provide first clues toward their contribution to the diverse protein functions and promise potential future applications in the area of nanotechnology. Combining the power of fully sequenced genomes and structure prediction algorithms, it is now possible to comprehensively summarize and compare the complete inventory of coiled-coil proteins of different organisms.Received 27 January 2004; received after revision 23 February 2004; accepted 10 March 2004     

New developments in the biological functions of lysophospholipids

Lysophospholipids have long been recognized as membrane phospholipid metabolites, but only recently has their role as intercellular signaling molecules been appreciated. Two of the best-studied lysophospholipids, LPA and S1P, signal through cognate G-protein-coupled receptors to activate many well-known intracellular signaling pathways, leading to a variety of biologically important cell responses. Lysophospholipids and their receptors have been found in a wide range of tissues and cell types, indicating their importance in many physiological processes, including reproduction, vascular development, cancer and nervous system function. This article will focus on the most recent findings regarding the biological functions of lysophospholipids in mammalian systems, specifically as they relate to health and disease. Received 5 April 2006; received after revision 22 June 2006; accepted 9 August 2006     

Bridging the molecular and biological functions of the oxysterol-binding protein family

Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) constitute a large eukaryotic gene family that transports and regulates the metabolism of sterols and phospholipids. The original classification of the family based on oxysterol-binding activity belies the complex dual lipid-binding specificity of the conserved OSBP homology domain (OHD). Additional protein- and membrane-interacting modules mediate the targeting of select OSBP/ORPs to membrane contact sites between organelles, thus positioning the OHD between opposing membranes for lipid transfer and metabolic regulation. This unique subcellular location, coupled with diverse ligand preferences and tissue distribution, has identified OSBP/ORPs as key arbiters of membrane composition and function. Here, we will review how molecular models of OSBP/ORP-mediated intracellular lipid transport and regulation at membrane contact sites relate to their emerging roles in cellular and organismal functions.     

Utilization of the pH-stat in the study of cellular metabolism

Riassunto È stata studiata la possibilità di seguire con un titolatore automatico impiegato come pH-stat l'andamento della respirazione e della glicolisi di cellule sopravviventi. I valori ottenuti sono in accordo con quelli descritti nella letteratura.Rispetto al metodo manometrico sono segnalati alcuni vantaggi quali la rapidità delle determinazioni, la possibilità di variare più parametri sperimentali nel corso dell'esperienza nonchè la facilità di prelievo di materiale durante l'esperimento.     

The subventricular zone: new molecular and cellular developments

The subventricular zone (SVZ), which lines the lateral walls of the lateral ventricle, persists as a neurogenic zone into adulthood and functions as the largest site of neurogenesis in the adult brain. In recent years, with the acceptance of the concept of postembryonic mammalian neurogenesis, neurogenesis in the adult SVZ has been an area of active research. With the rapid accumulation of new information on the SVZ, some of which is contradictory, summarizing existing knowledge on the SVZ and outlining future research directions in this area become important. In this review, we will cover recent molecular and cellular investigations that characterize the SVZ niche, SVZ neurogenesis, and SVZ cell migration within the adult brain.     

Structure of the gap junction channel and its implications for its biological functions

Gap junctions consist of arrays of intercellular channels composed of integral membrane proteins called connexin in vertebrates. Gap junction channels regulate the passage of ions and biological molecules between adjacent cells and, therefore, are critically important in many biological activities, including development, differentiation, neural activity, and immune response. Mutations in connexin genes are associated with several human diseases, such as neurodegenerative disease, skin disease, deafness, and developmental abnormalities. The activity of gap junction channels is regulated by the membrane voltage, intracellular microenvironment, interaction with other proteins, and phosphorylation. Each connexin channel has its own property for conductance and molecular permeability. A number of studies have tried to reveal the molecular architecture of the channel pore that should confer the connexin-specific permeability/selectivity properties and molecular basis for the gating and regulation. In this review, we give an overview of structural studies and describe the structural and functional relationship of gap junction channels.     

Extracellular Ca2+ and Mg2+ and cellular metabolism of phospholipids.

High extracellular concentration of Ca2+ inhibits the incorporation of 32P into the cellular phospholipids. This effect is more significant in neoplastic than in normal cells, and it is accompanied by an increase of the percentual incorporation into the lecithin fraction.