Special Issue "Trafficking of Membrane Receptors"

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A special issue of Membranes (ISSN 2077-0375). This special issue belongs to the section "Biological Membranes (Transport Processes)".

Deadline for manuscript submissions: closed (31 May 2014)

Special Issue Editors

Guest Editor
Dr. Morten S. Nielsen

Institut for Medicinsk Biokemi, Ole Worms Allé, Bygn. 170, Universitetsparken, 8000 Århus C, Denmark
Website | E-Mail
Fax: +45 861 31160
Interests: receptors; endocytosis; intracellular trafficking; lipoprotein; lipase
Guest Editor
Prof. Dr. Oddmund Bakke

Department of Molecular Biosciences, University of Oslo, Oslo 0316, Norway
Website | E-Mail
Phone: +47 2285 5787

Special Issue Information

Dear Colleagues,

Recently, the Nobel Prize in Physiology and Medicine was awarded to Dr. James E. Rothman, Dr. Randy W. Schekman and Dr. Thomas C. Südhof for their ground-breaking research concerning the regulation of vesicular traffic in eukaryotic cells. The vesicular system is used by membrane receptors for cellular trafficking; such trafficking includes exocytosis, endocytosis, transport in the endo-lysosomal system. After the receptors are incorporated into vesicles, subcellular trafficking including fusion, fission between vesicles, tubular structures from trans Golgi-network and endosomes and these complex events are all mediated by several adaptor and coat proteins (e.g., the Adaptor Complexes 1 to 4, the retromer complex, RAB proteins, and many others). Furthermore, active signaling within the endosomal pathway is of special interest for us. Also, asymmetric trafficking in polarized cells (e.g., epithelial and endothelial cells and neurons), adds an additional layer of complexity.

For this Special Issue of Membranes—“Trafficking of Membrane Receptors”, we encourage you to submit manuscripts discussing how the trafficking of recycling, retrograde-sorted, and other receptors is regulated in cells.

Dr. Morten S. Nielsen
Prof. Dr. Oddmund Bakke
Guest Editors

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Membranes is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 500 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.


Keywords

  • membrane receptors
  • anterograde traffic
  • retrograde traffic
  • endocytosis
  • exocytosis
  • adaptor proteins
  • coat proteins

Published Papers (12 papers)

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Review

Open AccessReview The Role of the Clathrin Adaptor AP-1: Polarized Sorting and Beyond
Membranes 2014, 4(4), 747-763; doi:10.3390/membranes4040747
Received: 8 July 2014 / Revised: 27 October 2014 / Accepted: 29 October 2014 / Published: 7 November 2014
Cited by 7 | PDF Full-text (606 KB) | HTML Full-text | XML Full-text
Abstract
The selective transport of proteins or lipids by vesicular transport is a fundamental process supporting cellular physiology. The budding process involves cargo sorting and vesicle formation at the donor membrane and constitutes an important process in vesicular transport. This process is particularly important
[...] Read more.
The selective transport of proteins or lipids by vesicular transport is a fundamental process supporting cellular physiology. The budding process involves cargo sorting and vesicle formation at the donor membrane and constitutes an important process in vesicular transport. This process is particularly important for the polarized sorting in epithelial cells, in which the cargo molecules need to be selectively sorted and transported to two distinct destinations, the apical or basolateral plasma membrane. Adaptor protein (AP)-1, a member of the AP complex family, which includes the ubiquitously expressed AP-1A and the epithelium-specific AP-1B, regulates polarized sorting at the trans-Golgi network and/or at the recycling endosomes. A growing body of evidence, especially from studies using model organisms and animals, demonstrates that the AP-1-mediated polarized sorting supports the development and physiology of multi-cellular units as functional organs and tissues (e.g., cell fate determination, inflammation and gut immune homeostasis). Furthermore, a possible involvement of AP-1B in the pathogenesis of human diseases, such as Crohn’s disease and cancer, is now becoming evident. These data highlight the significant contribution of AP-1 complexes to the physiology of multicellular organisms, as master regulators of polarized sorting in epithelial cells. Full article
(This article belongs to the Special Issue Trafficking of Membrane Receptors)
Open AccessReview The Role of Rab Proteins in Neuronal Cells and in the Trafficking of Neurotrophin Receptors
Membranes 2014, 4(4), 642-677; doi:10.3390/membranes4040642
Received: 8 July 2014 / Revised: 27 August 2014 / Accepted: 16 September 2014 / Published: 6 October 2014
Cited by 9 | PDF Full-text (1148 KB) | HTML Full-text | XML Full-text
Abstract
Neurotrophins are a family of proteins that are important for neuronal development, neuronal survival and neuronal functions. Neurotrophins exert their role by binding to their receptors, the Trk family of receptor tyrosine kinases (TrkA, TrkB, and TrkC) and p75NTR, a member of the
[...] Read more.
Neurotrophins are a family of proteins that are important for neuronal development, neuronal survival and neuronal functions. Neurotrophins exert their role by binding to their receptors, the Trk family of receptor tyrosine kinases (TrkA, TrkB, and TrkC) and p75NTR, a member of the tumor necrosis factor (TNF) receptor superfamily. Binding of neurotrophins to receptors triggers a complex series of signal transduction events, which are able to induce neuronal differentiation but are also responsible for neuronal maintenance and neuronal functions. Rab proteins are small GTPases localized to the cytosolic surface of specific intracellular compartments and are involved in controlling vesicular transport. Rab proteins, acting as master regulators of the membrane trafficking network, play a central role in both trafficking and signaling pathways of neurotrophin receptors. Axonal transport represents the Achilles' heel of neurons, due to the long-range distance that molecules, organelles and, in particular, neurotrophin-receptor complexes have to cover. Indeed, alterations of axonal transport and, specifically, of axonal trafficking of neurotrophin receptors are responsible for several human neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and some forms of Charcot-Marie-Tooth disease. In this review, we will discuss the link between Rab proteins and neurotrophin receptor trafficking and their influence on downstream signaling pathways. Full article
(This article belongs to the Special Issue Trafficking of Membrane Receptors)
Open AccessReview Calreticulin: Roles in Cell-Surface Protein Expression
Membranes 2014, 4(3), 630-641; doi:10.3390/membranes4030630
Received: 10 June 2014 / Revised: 5 September 2014 / Accepted: 9 September 2014 / Published: 16 September 2014
Cited by 6 | PDF Full-text (724 KB) | HTML Full-text | XML Full-text
Abstract
In order to perform their designated functions, proteins require precise subcellular localizations. For cell-surface proteins, such as receptors and channels, they are able to transduce signals only when properly targeted to the cell membrane. Calreticulin is a multi-functional chaperone protein involved in protein
[...] Read more.
In order to perform their designated functions, proteins require precise subcellular localizations. For cell-surface proteins, such as receptors and channels, they are able to transduce signals only when properly targeted to the cell membrane. Calreticulin is a multi-functional chaperone protein involved in protein folding, maturation, and trafficking. However, evidence has been accumulating that calreticulin can also negatively regulate the surface expression of certain receptors and channels. In these instances, depletion of calreticulin enhances cell-surface expression and function. In this review, we discuss the role of calreticulin with a focus on its negative effects on the expression of cell-surface proteins. Full article
(This article belongs to the Special Issue Trafficking of Membrane Receptors)
Open AccessReview Exocytosis and Endocytosis of Small Vesicles across the Plasma Membrane in Saccharomyces cerevisiae
Membranes 2014, 4(3), 608-629; doi:10.3390/membranes4030608
Received: 28 May 2014 / Revised: 2 August 2014 / Accepted: 18 August 2014 / Published: 3 September 2014
Cited by 2 | PDF Full-text (1611 KB) | HTML Full-text | XML Full-text
Abstract
When Saccharomyces cerevisiae is starved of glucose, the gluconeogenic enzymes fructose-1,6-bisphosphatase (FBPase), phosphoenolpyruvate carboxykinase, isocitrate lyase, and malate dehydrogenase, as well as the non-gluconeogenic enzymes glyceraldehyde-3-phosphate dehydrogenase and cyclophilin A, are secreted into the periplasm. In the extracellular fraction, these secreted proteins are
[...] Read more.
When Saccharomyces cerevisiae is starved of glucose, the gluconeogenic enzymes fructose-1,6-bisphosphatase (FBPase), phosphoenolpyruvate carboxykinase, isocitrate lyase, and malate dehydrogenase, as well as the non-gluconeogenic enzymes glyceraldehyde-3-phosphate dehydrogenase and cyclophilin A, are secreted into the periplasm. In the extracellular fraction, these secreted proteins are associated with small vesicles that account for more than 90% of the total number of extracellular structures observed. When glucose is added to glucose-starved cells, FBPase is internalized and associated with clusters of small vesicles in the cytoplasm. Specifically, the internalization of FBPase results in the decline of FBPase and vesicles in the extracellular fraction and their appearance in the cytoplasm. The clearance of extracellular vesicles and vesicle-associated proteins from the extracellular fraction is dependent on the endocytosis gene END3. This internalization is regulated when cells are transferred from low to high glucose. It is rapidly occurring and is a high capacity process, as clusters of vesicles occupy 10%–20% of the total volume in the cytoplasm in glucose re-fed cells. FBPase internalization also requires the VPS34 gene encoding PI3K. Following internalization, FBPase is delivered to the vacuole for degradation, whereas proteins that are not degraded may be recycled. Full article
(This article belongs to the Special Issue Trafficking of Membrane Receptors)
Open AccessReview Trafficking of Kainate Receptors
Membranes 2014, 4(3), 565-595; doi:10.3390/membranes4030565
Received: 6 July 2014 / Revised: 4 August 2014 / Accepted: 12 August 2014 / Published: 20 August 2014
Cited by 5 | PDF Full-text (998 KB) | HTML Full-text | XML Full-text
Abstract
Ionotropic glutamate receptors (iGluRs) mediate the vast majority of excitatory neurotransmission in the central nervous system of vertebrates. In the protein family of iGluRs, kainate receptors (KARs) comprise the probably least well understood receptor class. Although KARs act as key players in the
[...] Read more.
Ionotropic glutamate receptors (iGluRs) mediate the vast majority of excitatory neurotransmission in the central nervous system of vertebrates. In the protein family of iGluRs, kainate receptors (KARs) comprise the probably least well understood receptor class. Although KARs act as key players in the regulation of synaptic network activity, many properties and functions of these proteins remain elusive until now. Especially the precise pre-, extra-, and postsynaptic localization of KARs plays a critical role for neuronal function, as an unbalanced localization of KARs would ultimately lead to dysregulated neuronal excitability. Recently, important advances in the understanding of the regulation of surface expression, function, and agonist-dependent endocytosis of KARs have been achieved. Post-translational modifications like PKC-mediated phosphorylation and SUMOylation have been reported to critically influence surface expression and endocytosis, while newly discovered auxiliary proteins were shown to shape the functional properties of KARs. Full article
(This article belongs to the Special Issue Trafficking of Membrane Receptors)
Open AccessReview Trafficking of ThermoTRP Channels
Membranes 2014, 4(3), 525-564; doi:10.3390/membranes4030525
Received: 16 June 2014 / Revised: 11 July 2014 / Accepted: 8 August 2014 / Published: 19 August 2014
Cited by 9 | PDF Full-text (4009 KB) | HTML Full-text | XML Full-text
Abstract
ThermoTRP channels (thermoTRPs) define a subfamily of the transient receptor potential (TRP) channels that are activated by changes in the environmental temperature, from noxious cold to injurious heat. Acting as integrators of several stimuli and signalling pathways, dysfunction of these channels contributes to
[...] Read more.
ThermoTRP channels (thermoTRPs) define a subfamily of the transient receptor potential (TRP) channels that are activated by changes in the environmental temperature, from noxious cold to injurious heat. Acting as integrators of several stimuli and signalling pathways, dysfunction of these channels contributes to several pathological states. The surface expression of thermoTRPs is controlled by both, the constitutive and regulated vesicular trafficking. Modulation of receptor surface density during pathological processes is nowadays considered as an interesting therapeutic approach for management of diseases, such as chronic pain, in which an increased trafficking is associated with the pathological state. This review will focus on the recent advances trafficking of the thermoTRP channels, TRPV1, TRPV2, TRPV4, TRPM3, TRPM8 and TRPA1, into/from the plasma membrane. Particularly, regulated membrane insertion of thermoTRPs channels contributes to a fine tuning of final channel activity, and indeed, it has resulted in the development of novel therapeutic approaches with successful clinical results such as disruption of SNARE-dependent exocytosis by botulinum toxin or botulinomimetic peptides. Full article
(This article belongs to the Special Issue Trafficking of Membrane Receptors)
Figures

Open AccessReview Auxiliary Subunits: Shepherding AMPA Receptors to the Plasma Membrane
Membranes 2014, 4(3), 469-490; doi:10.3390/membranes4030469
Received: 16 June 2014 / Revised: 17 July 2014 / Accepted: 25 July 2014 / Published: 8 August 2014
Cited by 9 | PDF Full-text (2840 KB) | HTML Full-text | XML Full-text
Abstract
Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated cation channels that mediate excitatory signal transmission in the central nervous system (CNS) of vertebrates. The members of the iGluR subfamily of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate most of the fast excitatory signal transmission,
[...] Read more.
Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated cation channels that mediate excitatory signal transmission in the central nervous system (CNS) of vertebrates. The members of the iGluR subfamily of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate most of the fast excitatory signal transmission, and their abundance in the postsynaptic membrane is a major determinant of the strength of excitatory synapses. Therefore, regulation of AMPAR trafficking to the postsynaptic membrane is an important constituent of mechanisms involved in learning and memory formation, such as long-term potentiation (LTP) and long-term depression (LTD). Auxiliary subunits play a critical role in the facilitation and regulation of AMPAR trafficking and function. The currently identified auxiliary subunits of AMPARs are transmembrane AMPA receptor regulatory proteins (TARPs), suppressor of lurcher (SOL), cornichon homologues (CNIHs), synapse differentiation-induced gene I (SynDIG I), cysteine-knot AMPAR modulating proteins 44 (CKAMP44), and germ cell-specific gene 1-like (GSG1L) protein. In this review we summarize our current knowledge of the modulatory influence exerted by these important but still underappreciated proteins. Full article
(This article belongs to the Special Issue Trafficking of Membrane Receptors)
Open AccessReview The Mysterious Ways of ErbB2/HER2 Trafficking
Membranes 2014, 4(3), 424-446; doi:10.3390/membranes4030424
Received: 27 May 2014 / Revised: 1 July 2014 / Accepted: 22 July 2014 / Published: 6 August 2014
Cited by 13 | PDF Full-text (744 KB) | HTML Full-text | XML Full-text
Abstract
The EGFR- or ErbB-family of receptor tyrosine kinases consists of EGFR/ErbB1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4. Receptor activation and downstream signaling are generally initiated upon ligand-induced receptor homo- or heterodimerization at the plasma membrane, and endocytosis and intracellular membrane transport are crucial for regulation
[...] Read more.
The EGFR- or ErbB-family of receptor tyrosine kinases consists of EGFR/ErbB1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4. Receptor activation and downstream signaling are generally initiated upon ligand-induced receptor homo- or heterodimerization at the plasma membrane, and endocytosis and intracellular membrane transport are crucial for regulation of the signaling outcome. Among the receptors, ErbB2 is special in several ways. Unlike the others, ErbB2 has no known ligand, but is still the favored dimerization partner. Furthermore, while the other receptors are down-regulated either constitutively or upon ligand-binding, ErbB2 is resistant to down-regulation, and also inhibits down-regulation of its partner upon heterodimerization. The reason(s) why ErbB2 is resistant to down-regulation are the subject of debate. Contrary to other ErbB-proteins, mature ErbB2 needs Hsp90 as chaperone. Several data suggest that Hsp90 is an important regulator of factors like ErbB2 stability, dimerization and/or signaling. Hsp90 inhibitors induce degradation of ErbB2, but whether Hsp90 directly makes ErbB2 endocytosis resistant is unclear. Exposure to anti-ErbB2 antibodies can also induce down-regulation of ErbB2. Down-regulation induced by Hsp90 inhibitors or antibodies does at least partly involve internalization and endosomal sorting to lysosomes for degradation, but also retrograde trafficking to the nucleus has been reported. In this review, we will discuss different molecular mechanisms suggested to be important for making ErbB2 resistant to down-regulation, and review how membrane trafficking is involved when down-regulation and/or relocalization of ErbB2 is induced. Full article
(This article belongs to the Special Issue Trafficking of Membrane Receptors)
Figures

Open AccessReview The Biochemical Properties and Functions of CALM and AP180 in Clathrin Mediated Endocytosis
Membranes 2014, 4(3), 388-413; doi:10.3390/membranes4030388
Received: 5 June 2014 / Revised: 3 July 2014 / Accepted: 22 July 2014 / Published: 31 July 2014
PDF Full-text (1929 KB) | HTML Full-text | XML Full-text
Abstract
Clathrin-mediated endocytosis (CME) is a fundamental process for the regulated internalization of transmembrane cargo and ligands via the formation of vesicles using a clathrin coat. A vesicle coat is initially created at the plasma membrane by clathrin assembly into a lattice, while a
[...] Read more.
Clathrin-mediated endocytosis (CME) is a fundamental process for the regulated internalization of transmembrane cargo and ligands via the formation of vesicles using a clathrin coat. A vesicle coat is initially created at the plasma membrane by clathrin assembly into a lattice, while a specific cargo sorting process selects and concentrates proteins for inclusion in the new vesicle. Vesicles formed via CME traffic to different parts of the cell and fuse with target membranes to deliver cargo. Both clathrin assembly and cargo sorting functions are features of the two gene family consisting of assembly protein 180 kDa (AP180) and clathrin assembly lymphoid myeloid leukemia protein (CALM). In this review, we compare the primary structure and domain organization of CALM and AP180 and relate these properties to known functions and roles in CME and disease. Full article
(This article belongs to the Special Issue Trafficking of Membrane Receptors)
Figures

Open AccessReview The Endocytic Receptor Megalin and its Associated Proteins in Proximal Tubule Epithelial Cells
Membranes 2014, 4(3), 333-355; doi:10.3390/membranes4030333
Received: 31 May 2014 / Revised: 23 June 2014 / Accepted: 1 July 2014 / Published: 11 July 2014
Cited by 5 | PDF Full-text (639 KB) | HTML Full-text | XML Full-text
Abstract
Receptor-mediated endocytosis in renal proximal tubule epithelial cells (PTECs) is important for the reabsorption and metabolization of proteins and other substances, including carrier-bound vitamins and trace elements, in glomerular filtrates. Impairment of this endocytic process results in the loss of such substances and
[...] Read more.
Receptor-mediated endocytosis in renal proximal tubule epithelial cells (PTECs) is important for the reabsorption and metabolization of proteins and other substances, including carrier-bound vitamins and trace elements, in glomerular filtrates. Impairment of this endocytic process results in the loss of such substances and development of proteinuria, which is an important clinical indicator of kidney diseases and is also a risk marker for cardiovascular disease. Megalin, a member of the low-density lipoprotein receptor gene family, is a multiligand receptor expressed in the apical membrane of PTECs and plays a central role in the endocytic process. Megalin interacts with various intracellular adaptor proteins for intracellular trafficking and cooperatively functions with other membrane molecules, including the cubilin-amnionless complex. Evidence suggests that megalin and the cubilin-amnionless complex are involved in the uptake of toxic substances into PTECs, which leads to the development of kidney disease. Studies of megalin and its associated molecules will be useful for future development of novel strategies for the diagnosis and treatment of kidney diseases. Full article
(This article belongs to the Special Issue Trafficking of Membrane Receptors)
Open AccessReview Endocytic Trafficking of Membrane-Bound Cargo: A Flotillin Point of View
Membranes 2014, 4(3), 356-371; doi:10.3390/membranes4030356
Received: 26 May 2014 / Revised: 28 June 2014 / Accepted: 2 July 2014 / Published: 11 July 2014
Cited by 7 | PDF Full-text (612 KB) | HTML Full-text | XML Full-text
Abstract
The ubiquitous and highly conserved flotillin proteins, flotillin-1 and flotillin-2, have been shown to be involved in various cellular processes such as cell adhesion, signal transduction through receptor tyrosine kinases as well as in cellular trafficking pathways. Due to the fact that flotillins
[...] Read more.
The ubiquitous and highly conserved flotillin proteins, flotillin-1 and flotillin-2, have been shown to be involved in various cellular processes such as cell adhesion, signal transduction through receptor tyrosine kinases as well as in cellular trafficking pathways. Due to the fact that flotillins are acylated and form hetero-oligomers, they constitutively associate with cholesterol-enriched lipid microdomains. In recent years, such microdomains have been appreciated as platforms that participate in endocytosis and other cellular trafficking steps. This review summarizes the current findings on the role of flotillins in membrane-bound cargo endocytosis and endosomal trafficking events. We will discuss the proposed function of flotillins in endocytosis in the light of recent findings that point towards a role for flotillins in a step that precedes the actual endocytic uptake of cargo molecules. Recent findings have also revealed that flotillins may be important for endosomal sorting and recycling of specific cargo molecules. In addition to these aspects, the cellular trafficking pathway of flotillins themselves as potential cargo in the context of growth factor signaling will be discussed. Full article
(This article belongs to the Special Issue Trafficking of Membrane Receptors)
Figures

Open AccessReview Role of Phospholipase D in G-Protein Coupled Receptor Function
Membranes 2014, 4(3), 302-318; doi:10.3390/membranes4030302
Received: 29 May 2014 / Revised: 24 June 2014 / Accepted: 25 June 2014 / Published: 3 July 2014
Cited by 3 | PDF Full-text (703 KB) | HTML Full-text | XML Full-text
Abstract
Prolonged agonist exposure of many G-protein coupled receptors induces a rapid receptor phosphorylation and uncoupling from G-proteins. Resensitization of these desensitized receptors requires endocytosis and subsequent dephosphorylation. Numerous studies show the involvement of phospholipid-specific phosphodiesterase phospholipase D (PLD) in the receptor endocytosis and
[...] Read more.
Prolonged agonist exposure of many G-protein coupled receptors induces a rapid receptor phosphorylation and uncoupling from G-proteins. Resensitization of these desensitized receptors requires endocytosis and subsequent dephosphorylation. Numerous studies show the involvement of phospholipid-specific phosphodiesterase phospholipase D (PLD) in the receptor endocytosis and recycling of many G-protein coupled receptors e.g., opioid, formyl or dopamine receptors. The PLD hydrolyzes the headgroup of a phospholipid, generally phosphatidylcholine (PC), to phosphatidic acid (PA) and choline and is assumed to play an important function in cell regulation and receptor trafficking. Protein kinases and GTP binding proteins of the ADP-ribosylation and Rho families regulate the two mammalian PLD isoforms 1 and 2. Mammalian and yeast PLD are also potently stimulated by phosphatidylinositol 4,5-bisphosphate. The PA product is an intracellular lipid messenger. PLD and PA activities are implicated in a wide range of physiological processes and diseases including inflammation, diabetes, oncogenesis or neurodegeneration. This review discusses the characterization, structure, and regulation of PLD in the context of membrane located G-protein coupled receptor function. Full article
(This article belongs to the Special Issue Trafficking of Membrane Receptors)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review
Title: Role of Phospholipase D in G-protein Coupled Receptor Function
Author: Lars-Ove Brandenburg
Affiliation: Department of Anatomy and Cell Biology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany; E-Mail: lbrandenburg@ukaachen.de
Abstract: Agonist exposure of many G-protein coupled receptors induces a rapid receptor phosphorylation and uncoupling from G-proteins. Resensitization of these desensitized receptors requires endocytosis and subsequent dephosphorylation. Several works shows the involvement of phospholipid-specific phosphodiesterase phospholipase D (PLD) in the receptor endocytosis and recycling of many G-protein coupled receptors e.g. opioid, formyl or dopamine receptors. The PLD hydrolyzes the headgroup of a phospholipid, generally phosphatidylcholine (PC) to phosphatidic acid (PA) and choline and is assumed to play an important function in cell regulation and receptor trafficking. The two mammalian PLD isoforms 1 and 2 are regulated by protein kinases and GTP binding proteins of the ADP-ribosylation and Rho families. Mammalian and yeast PLD are also potently stimulated by phosphatidylinositol 4,5-bisphosphate. The PA product is an intracellular lipid messenger. PLD and PA activities are implicated in a wide range of physiological processes and diseases including inflammation, diabetes, oncogenesis or neurodegeneration. This review discusses the characterization, structure, regulation of PLD in the context of membrane located G-protein coupled receptor function.

Type of Paper: Review
Title: Road not Taken: Which Way to Chose from the TGN to the Plasma Membrane?
Author: Anne Spang
Affiliation: Biozentrum, Growth & Development, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland; E-Mail: anne.spang@unibas.ch
Abstract: The trans-Golgi network functions in the distribution of cargo into different transport vesicles that are destined to the endosomes, lysosomes and the plasma membrane. Over the years it became clear that there are at least two, if not more, transport pathways promoting plasma membrane localization of proteins. In spite of the importance temporal and spatial control of protein localization at the plasma membrane, the regulation of sorting into and the formation of different transport containers are still poorly understood. This review summarizes the current knowledge about the different transport pathway and discusses concepts of regulation and sorting at the TGN.

Type of Paper: Review
Title: Intracellular Trafficking of Antisense and siRNA Oligonucleotides
Author: Rudy Juliano
Affiliation: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; E-Mail: rudy_juliano@med.unc.edu
Abstract: One of the major limitations on the therapeutic use of antisense and siRNA oligonucleotides is inefficient delivery to their sites of action in the cytosol or nucleus. It is clear that the pathways of cellular uptake and intracellular trafficking of oligonucleotides can strongly influence their pharmacological actions. Here we review current information on the basic processes of subcellular trafficking of oligonucleotides in the context of the implications for therapy.

Type of Paper: Review
Title:
Endocytic Receptor Megalin and its Associated Proteins in Proximal Tubule Epithelial Cells
Author:
Akihiko Saito
Affiliation:
Department of Applied Molecular Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan; E-Mail: akisaito@med.niigata-u.ac.jp
Abstract:
Receptor-mediated endocytosis is an important function of renal proximal tubule epithelial cells (PTECs) to reabsorb and metabolize proteins and other substances in glomerular filtrates. The function is involved in the conservation of nutrients, including carrier-bound vitamins and trace elements. Impairment of the process results in a loss of such substances and development of proteinuria, an important clinical sign of kidney disease and a risk marker for cardiovascular disease. Megalin, a member of the LDL receptor gene family, is a multiligand receptor expressed at clathrin-coated pits of PTECs and plays a central role in the endocyotic functions. Megalin interacts with various intracellular adaptor proteins for intracellular trafficking and cooperates with other membrane molecules such as cubilin-amnionless complex. Megalin and cubilin-amnionless complex may be involved in uptake of some toxic substances into PTECs, participating in the development of kidney diseases. Megalin is excreted into urine in soluble and insoluble forms, which are both being used as clinical biomarkers. Studies of megalin and its associated molecules will be useful for the future development of novel strategies for diagnosis and treatment of kidney diseases.

Type of Paper: Review
Title:
Review of the Influence of Auxiliary Subunits on the Forward Trafficking of AMPA Subtype Glutamate Receptors
Author
s: Simon Koesters 1,2,3 and Michael Hollmann 1
Affiliation:
1 Department of Biochemistry I—Receptorbiochemistry, Ruhr-University Bochum, Germany; E-Mail: Simon.Koesters@ruhr-uni-bochum.de
2
Graduate School of Chemistry and Biochemistry (GSCB), Ruhr-University Bochum, Germany
3
RUB Research School Plus, Ruhr-University Bochum, Germany
Abstract:
Ionotropic glutamate receptors (iGluR) are responsible for a mayor part of the excitatory signal transmission in the central nervous system (CNS). The iGluR protein family, based on pharmacological properties and sequence homologies, is subdivided into several different subclasses including NMDA receptors (GluN), AMPA receptors (GluA), kainate receptors (GluK), and delta receptors (GluD). Among these subclasses AMPA receptors are responsible for modifying the synaptic strength via fast regulation and relocation of AMPA receptors at the postsynaptic density (PSD) during plasticity-generating events such as long term depression (LTD) and long term potentiation (LTP). Critically important for these properties are auxiliary subunits such as the transmembrane AMPA receptor regulatory proteins (TARPs). However, within the last decade many additional auxiliary subunits of AMPA receptors have been discovered, including the cornichons (CNIH2/-3), CKAMP44, the SynDig protein family, SOL-1/-2, and GSG-1L. These proteins modify the electrophysiological and pharmacological properties of the receptor and some of them are responsible for the transport of the receptor to the cell membrane and the localization at the PSD of the synapse. In this review we are focusing on these interactions and the influence of auxiliary subunits on the trafficking and the localization of AMPA receptors in glutamatergic synapses.

Type of Paper: Review
Title: Calreticulin: Roles on Cell-Surface Protein Expression
Authors: Yue Jiang and Hiroaki Matsunami*
Affiliation: Department of Molecular Genetics and Microbiology and Department of Neurobiology, Duke Institute for Brain Sciences, Duke University Medical Center, Box 3054, 264 CARL Bldg., 213 Research Dr., Durham, NC 27710, USA; E-Mail: hiroaki.matsunami@duke.edu
Abstract: In order to perform their designated functions, proteins require precise subcellular localizations. This is especially true for cell-surface proteins, such as receptors and channels: they are able to transducer signals between the interior and exterior of the cell only when properly targeted to the cell membrane. Calreticulin is a multi-functional chaperone protein involved in protein folding, maturation and trafficking. However, evidence has been accumulating that calreticulin can also negatively regulate the surface expression of certain receptors and channels. For these instances, depletion of calreticulin enhances their cell-surface expression and function. In this review, we discuss the role of calreticulin with focus on its negative effects on the expression of cell-surface proteins.

Type of Paper: Article
Title: KLHL1 Promotes Recycling of Voltage-Gated T-type Channel CaV3.2 to the Plasma Membrane
Author: Erika Piedras-Rentería
Affiliation: Department of Cellular and Molecular Physiology, Neuroscience Institute, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA; E-Mail: erikapiedras@me.com

Type of Paper: Review
T
itle: Trafficking of Kainate Receptors
Authors:
Steffen Pahl 1,2,3,* and Michael Hollmann 1,2
Affiliation
s: 1 Department of Biochemistry I, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Germany; E-Mail: steffen.pahl@rub.de
2
International Graduate School of Neuroscience, Ruhr University Bochum, Germany
3
Ruhr University Research School, Ruhr University Bochum
Abstract:
Ionotropic glutamate receptors (iGluRs) mediate the vast majority of excitatory neurotransmission in the central nervous system of vertebrates. In the protein family of iGluRs, kainate receptors (KARs) comprise the probably least well understood receptor class. Although KARs act as key players in the regulation of synaptic network activity, many properties and functions of these proteins remain elusive until now. Especially the precise pre-, extra-, and postsynaptic localization of KARs plays an important and at the same time critical role for neuronal function, and a disbalanced localization of KARs would ultimately lead to disregulated neuronal excitability.
Recently, important advances in the understanding of the regulation of surface expression, function, and agonist-dependent endocytosis of KARs have been achieved. For example, post-translational modifications like PKC-mediated phosphorylation and SUMOylation have been reported to critically influence surface expression and endocytosis, while newly discovered auxiliary proteins were shown to shape the function of KARs.
This review will mainly focus on the mechanisms involved in surface expression and endocytosis of the receptors, with an emphasis on data that has been published since 2010.

Type of Paper: Review
Title:
The Endocytic Trafficking of Membrane-Bound Cargo: A Flotillin Point of View
Authors:
Melanie Meister and Ritva Tikkanen *
Affiliation:
Institute of Biochemistry, University of Giessen, Giessen, Germany; E-Mail: Ritva.Tikkanen@biochemie.med.uni-giessen.de
Abstract: The ubiquitous and highly conserved flotillin proteins, flotillin-1 and flotillin-2, have been shown to be involved in various cellular processes such as cellular adhesion, signal transduction through receptor tyrosine kinases as well as in cellular trafficking pathways. Due to the fact that flotillins are acylated and form hetero-oligomers, they constitutively associate with cholesterol-enriched lipid microdomains. In the recent years, such microdomains have been appreciated as platforms that participate in endocytosis and other cellular trafficking steps. This review summarizes the current findings on the role of flotillins in cargo endocytosis and endosomal trafficking events. We will discuss the proposed function of flotillins in endocytosis in the light of recent findings that point towards a role for flotillins in a step that precedes the actual endocytosis of cargo molecules. Recent findings have also revealed that flotillins may be important for endosomal sorting and recycling of specific cargo molecules. In addition to these aspects, the cellular trafficking pathway of flotillins themselves as potential cargo in the context of growth factor stimulation will be dissected.

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