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Themed Issue in Honor of Carlos Gutiérrez Merino: Forty Years of Research Excellence in the Field of Membrane Proteins and Bioenergetics

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: 20 August 2024 | Viewed by 21832

Special Issue Editors


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Guest Editor
CSIC-UAM - Instituto de Investigaciones Biomédicas Alberto Sols (IIBM), Madrid, Spain
Interests: free radical biology; reactive oxygen species; reactive nitrogen species; peroxidases; NADH oxidases; lipidomics; intrinsically disordered proteins; neurodegenerative diseases; redox biomedicine
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Guest Editor
Department of Human Anatomy and Embryology, Faculty of Medicine, Institute of Molecular Pathology Biomarkers, University of Extremadura, 06006 Badajoz, Spain
Interests: cardiovascular development; gastrulation; gene expression patterns; microRNAs; signaling pathways; experimental models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As a Guest Editor of this Special Issue it is a pleasure to welcome your contributions dedicated to Prof. Carlos Gutierrez Merino, who has nearly reached the 40th anniversary of his research track and has dedicated his life to studying membrane proteins’ structure and function as well as their connection to cell bioenergetics and metabolism. Besides his outstanding career, Prof. Carlos Merino has been an excellent mentor, with whom it has been a pleasure to work.

Prof. Carlos Gutierrez Merino obtained his licentiate degree in Chemistry in 1974 at the Universidad Complutense de Madrid, and was immediately incorporated into the CSIC as a predoctoral student in 1975. He defended his PhD thesis in 1977. After a short stage as a lecturer at the Universidad Autónoma de Barcelona, he moved to the United States in 1978 to the Department of Pharmacology and Biochemistry in the Faculty of Medicine at the University of Virginia. He obtained an Assistant Professor position in 1981 in the Biochemistry and Molecular Biology Department at the School of Sciences at the Universidad de Extremadura and later Associate Professor and full Professor positions in 1985 and 1989, respectively. He was also Director of the Biochemistry and Molecular Biology Department from 1987 to 1995 and Research Vice-Rector at the University of Extremadura from 1995 to 1999. He was also a Board Member of the Spanish Biophysical Society in the 1990s.

He has an h-factor of 32 with more than 160 scientific publications and more than 100 peer-reviewed research articles. He has mentored 18 PhD students. He has made major scientific advances in the study of membrane proteins’ structure and function. These include Ca2+-ATPase pumps, plasma membrane L-type calcium channels, microsomal cytochrome P450s reductase, and plasma membrane cytochrome b5 reductase, as well as metalloproteins, glycogen phosphorylase, natural antioxidants, Aβ amyloid peptides and the functional characterization of the neuronal plasma membrane nanodomains.

To honor Prof. Carlos Gutierrez Merino’s research work during his outstanding career, we invite contributions from Ph.D. students, collaborators, and friends in the broad range of disciplines in which he has made contributions.

Dr. Alejandro Samhan-Arias
Prof. Dr. Manuel Aureliano
Dr. Carmen Lopez-Sanchez
Guest Editors

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Keywords

  • membrane proteins
  • bioenergetics
  • metalloproteins
  • natural antioxidants
  • calcium signaling

Published Papers (13 papers)

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Research

Jump to: Review

17 pages, 2268 KiB  
Article
Cardiolipin Membranes Promote Cytochrome c Transformation of Polycyclic Aromatic Hydrocarbons and Their In Vivo Metabolites
by João Lopes, Dorinda Marques-da-Silva, Paula A. Videira, Alejandro K. Samhan-Arias and Ricardo Lagoa
Molecules 2024, 29(5), 1129; https://doi.org/10.3390/molecules29051129 - 03 Mar 2024
Viewed by 656
Abstract
The catalytic properties of cytochrome c (Cc) have captured great interest in respect to mitochondrial physiology and apoptosis, and hold potential for novel enzymatic bioremediation systems. Nevertheless, its contribution to the metabolism of environmental toxicants remains unstudied. Human exposure to polycyclic [...] Read more.
The catalytic properties of cytochrome c (Cc) have captured great interest in respect to mitochondrial physiology and apoptosis, and hold potential for novel enzymatic bioremediation systems. Nevertheless, its contribution to the metabolism of environmental toxicants remains unstudied. Human exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with impactful diseases, and animal models have unveiled concerning signs of PAHs’ toxicity to mitochondria. In this work, a series of eight PAHs with ionization potentials between 7.2 and 8.1 eV were used to challenge the catalytic ability of Cc and to evaluate the effect of vesicles containing cardiolipin mimicking mitochondrial membranes activating the peroxidase activity of Cc. With moderate levels of H2O2 and at pH 7.0, Cc catalyzed the oxidation of toxic PAHs, such as benzo[a]pyrene, anthracene, and benzo[a]anthracene, and the cardiolipin-containing membranes clearly increased the PAH conversions. Our results also demonstrate for the first time that Cc and Cc–cardiolipin complexes efficiently transformed the PAH metabolites 2-hydroxynaphthalene and 1-hydroxypyrene. In comparison to horseradish peroxidase, Cc was shown to reach more potent oxidizing states and react with PAHs with ionization potentials up to 7.70 eV, including pyrene and acenaphthene. Spectral assays indicated that anthracene binds to Cc, and docking simulations proposed possible binding sites positioning anthracene for oxidation. The results give support to the participation of Cc in the metabolism of PAHs, especially in mitochondria, and encourage further investigation of the molecular interaction between PAHs and Cc. Full article
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20 pages, 2828 KiB  
Article
Hexa-Histidine, a Peptide with Versatile Applications in the Study of Amyloid-β(1–42) Molecular Mechanisms of Action
by Jairo Salazar, Alejandro K. Samhan-Arias and Carlos Gutierrez-Merino
Molecules 2023, 28(20), 7138; https://doi.org/10.3390/molecules28207138 - 17 Oct 2023
Cited by 2 | Viewed by 780
Abstract
Amyloid β (Aβ) oligomers are the most neurotoxic forms of Aβ, and Aβ(1–42) is the prevalent Aβ peptide found in the amyloid plaques of Alzheimer’s disease patients. Aβ(25–35) is the shortest peptide that retains the toxicity of Aβ(1–42). Aβ oligomers bind to calmodulin [...] Read more.
Amyloid β (Aβ) oligomers are the most neurotoxic forms of Aβ, and Aβ(1–42) is the prevalent Aβ peptide found in the amyloid plaques of Alzheimer’s disease patients. Aβ(25–35) is the shortest peptide that retains the toxicity of Aβ(1–42). Aβ oligomers bind to calmodulin (CaM) and calbindin-D28k with dissociation constants in the nanomolar Aβ(1–42) concentration range. Aβ and histidine-rich proteins have a high affinity for transition metal ions Cu2+, Fe3+ and Zn2+. In this work, we show that the fluorescence of Aβ(1–42) HiLyteTM-Fluor555 can be used to monitor hexa-histidine peptide (His6) interaction with Aβ(1–42). The formation of His6/Aβ(1–42) complexes is also supported by docking results yielded by the MDockPeP Server. Also, we found that micromolar concentrations of His6 block the increase in the fluorescence of Aβ(1–42) HiLyteTM-Fluor555 produced by its interaction with the proteins CaM and calbindin-D28k. In addition, we found that the His6-tag provides a high-affinity site for the binding of Aβ(1–42) and Aβ(25–35) peptides to the human recombinant cytochrome b5 reductase, and sensitizes this enzyme to inhibition by these peptides. In conclusion, our results suggest that a His6-tag could provide a valuable new tool to experimentally direct the action of neurotoxic Aβ peptides toward selected cellular targets. Full article
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16 pages, 3105 KiB  
Article
Store-Operated Calcium Entry Inhibition and Plasma Membrane Calcium Pump Upregulation Contribute to the Maintenance of Resting Cytosolic Calcium Concentration in A1-like Astrocytes
by Joana Poejo, María Berrocal, Lucía Saez, Carlos Gutierrez-Merino and Ana M. Mata
Molecules 2023, 28(14), 5363; https://doi.org/10.3390/molecules28145363 - 12 Jul 2023
Viewed by 1331
Abstract
Highly neurotoxic A1-reactive astrocytes have been associated with several human neurodegenerative diseases. Complement protein C3 expression is strongly upregulated in A1 astrocytes, and this protein has been shown to be a specific biomarker of these astrocytes. Several cytokines released in neurodegenerative diseases have [...] Read more.
Highly neurotoxic A1-reactive astrocytes have been associated with several human neurodegenerative diseases. Complement protein C3 expression is strongly upregulated in A1 astrocytes, and this protein has been shown to be a specific biomarker of these astrocytes. Several cytokines released in neurodegenerative diseases have been shown to upregulate the production of amyloid β protein precursor (APP) and neurotoxic amyloid β (Aβ) peptides in reactive astrocytes. Also, aberrant Ca2+ signals have been proposed as a hallmark of astrocyte functional remodeling in Alzheimer’s disease mouse models. In this work, we induced the generation of A1-like reactive astrocytes after the co-treatment of U251 human astroglioma cells with a cocktail of the cytokines TNF-α, IL1-α and C1q. These A1-like astrocytes show increased production of APP and Aβ peptides compared to untreated U251 cells. Additionally, A1-like astrocytes show a (75 ± 10)% decrease in the Ca2+ stored in the endoplasmic reticulum (ER), (85 ± 10)% attenuation of Ca2+ entry after complete Ca2+ depletion of the ER, and three-fold upregulation of plasma membrane calcium pump expression, with respect to non-treated Control astrocytes. These altered intracellular Ca2+ dynamics allow A1-like astrocytes to efficiently counterbalance the enhanced release of Ca2+ from the ER, preventing a rise in the resting cytosolic Ca2+ concentration. Full article
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16 pages, 4860 KiB  
Article
New Functions of Intracellular LOXL2: Modulation of RNA-Binding Proteins
by Pilar Eraso, María J. Mazón, Victoria Jiménez, Patricia Pizarro-García, Eva P. Cuevas, Jara Majuelos-Melguizo, Jesús Morillo-Bernal, Amparo Cano and Francisco Portillo
Molecules 2023, 28(11), 4433; https://doi.org/10.3390/molecules28114433 - 30 May 2023
Cited by 3 | Viewed by 1386
Abstract
Lysyl oxidase-like 2 (LOXL2) was initially described as an extracellular enzyme involved in extracellular matrix remodeling. Nevertheless, numerous recent reports have implicated intracellular LOXL2 in a wide variety of processes that impact on gene transcription, development, differentiation, proliferation, migration, cell adhesion, and angiogenesis, [...] Read more.
Lysyl oxidase-like 2 (LOXL2) was initially described as an extracellular enzyme involved in extracellular matrix remodeling. Nevertheless, numerous recent reports have implicated intracellular LOXL2 in a wide variety of processes that impact on gene transcription, development, differentiation, proliferation, migration, cell adhesion, and angiogenesis, suggesting multiple different functions for this protein. In addition, increasing knowledge about LOXL2 points to a role in several types of human cancer. Moreover, LOXL2 is able to induce the epithelial-to-mesenchymal transition (EMT) process—the first step in the metastatic cascade. To uncover the underlying mechanisms of the great variety of functions of intracellular LOXL2, we carried out an analysis of LOXL2’s nuclear interactome. This study reveals the interaction of LOXL2 with numerous RNA-binding proteins (RBPs) involved in several aspects of RNA metabolism. Gene expression profile analysis of cells silenced for LOXL2, combined with in silico identification of RBPs’ targets, points to six RBPs as candidates to be substrates of LOXL2’s action, and that deserve a more mechanistic analysis in the future. The results presented here allow us to hypothesize novel LOXL2 functions that might help to comprehend its multifaceted role in the tumorigenic process. Full article
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5 pages, 750 KiB  
Communication
Mechanical Properties of 3-Hydroxybutyric Acid-Induced Vesicles
by Seung Jun Jung, Kunn Hadinoto and Jin-Won Park
Molecules 2023, 28(6), 2742; https://doi.org/10.3390/molecules28062742 - 17 Mar 2023
Viewed by 995
Abstract
The vesicle mechanical behaviors were studied upon its exposure to 3-hydroxybutyric acid using an atomic force microscope (AFM). Dipalmitoylphosphatidylcholine (DPPC) and 3-hydroxybutyric acid were used to manufacture the vesicles at their desired ratio. The deflection of an AFM probe with respect to its [...] Read more.
The vesicle mechanical behaviors were studied upon its exposure to 3-hydroxybutyric acid using an atomic force microscope (AFM). Dipalmitoylphosphatidylcholine (DPPC) and 3-hydroxybutyric acid were used to manufacture the vesicles at their desired ratio. The deflection of an AFM probe with respect to its displacement was measured after characterizing the vesicle adsorption. The movement was analyzed with the Hertzian model to understand the physical behavior of the vesicles. However, in the deflection just prior to the first penetration, the model was a good fit, and the vesicle mechanical moduli were calculated. The moduli became lower with the higher ratio of 3-hydroxybutyric acid to DPPC, but the moduli were saturated at 0.5 of the ratio. These results appear to be the basis for the function of the metabolism associated with 3-hydroxybutyric acid, i.e., anesthetization and glycemic control, on the physical properties of cell membranes. Full article
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7 pages, 1007 KiB  
Article
Resazurin Reduction-Based Assays Revisited: Guidelines for Accurate Reporting of Relative Differences on Metabolic Status
by Beatriz Vieira-da-Silva and Miguel A. R. B. Castanho
Molecules 2023, 28(5), 2283; https://doi.org/10.3390/molecules28052283 - 01 Mar 2023
Cited by 9 | Viewed by 3098
Abstract
Cell viability and metabolic activity are ubiquitous parameters used in biochemistry, molecular biology, and biotechnological studies. Virtually all toxicology and pharmacological projects include at some point the evaluation of cell viability and/or metabolic activity. Among the methods used to address cell metabolic activity, [...] Read more.
Cell viability and metabolic activity are ubiquitous parameters used in biochemistry, molecular biology, and biotechnological studies. Virtually all toxicology and pharmacological projects include at some point the evaluation of cell viability and/or metabolic activity. Among the methods used to address cell metabolic activity, resazurin reduction is probably the most common. At variance with resazurin, resorufin is intrinsically fluorescent, which simplifies its detection. Resazurin conversion to resorufin in the presence of cells is used as a reporter of metabolic activity of cells and can be detected by a simple fluorometric assay. UV–Vis absorbance is an alternative technique but is not as sensitive. In contrast to its wide empirical “black box” use, the chemical and cell biology fundamentals of the resazurin assay are underexplored. Resorufin is further converted to other species, which jeopardizes the linearity of the assays, and the interference of extracellular processes has to be accounted for when quantitative bioassays are aimed at. In this work, we revisit the fundamentals of metabolic activity assays based on the reduction of resazurin. Deviation to linearity both in calibration and kinetics, as well as the existence of competing reactions for resazurin and resorufin and their impact on the outcome of the assay, are addressed. In brief, fluorometric ratio assays using low resazurin concentrations obtained from data collected at short time intervals are proposed to ensure reliable conclusions. Full article
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Review

Jump to: Research

16 pages, 1341 KiB  
Review
Carlos Gutiérrez-Merino: Synergy of Theory and Experimentation in Biological Membrane Research
by Silvia S. Antollini and Francisco J. Barrantes
Molecules 2024, 29(4), 820; https://doi.org/10.3390/molecules29040820 - 10 Feb 2024
Viewed by 662
Abstract
Professor Carlos Gutiérrez-Merino, a prominent scientist working in the complex realm of biological membranes, has made significant theoretical and experimental contributions to the field. Contemporaneous with the development of the fluid-mosaic model of Singer and Nicolson, the Förster resonance energy transfer (FRET) approach [...] Read more.
Professor Carlos Gutiérrez-Merino, a prominent scientist working in the complex realm of biological membranes, has made significant theoretical and experimental contributions to the field. Contemporaneous with the development of the fluid-mosaic model of Singer and Nicolson, the Förster resonance energy transfer (FRET) approach has become an invaluable tool for studying molecular interactions in membranes, providing structural insights on a scale of 1–10 nm and remaining important alongside evolving perspectives on membrane structures. In the last few decades, Gutiérrez-Merino’s work has covered multiple facets in the field of FRET, with his contributions producing significant advances in quantitative membrane biology. His more recent experimental work expanded the ground concepts of FRET to high-resolution cell imaging. Commencing in the late 1980s, a series of collaborations between Gutiérrez-Merino and the authors involved research visits and joint investigations focused on the nicotinic acetylcholine receptor and its relation to membrane lipids, fostering a lasting friendship. Full article
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21 pages, 1815 KiB  
Review
Trabectedin and Lurbinectedin Modulate the Interplay between Cells in the Tumour Microenvironment—Progresses in Their Use in Combined Cancer Therapy
by Adrián Povo-Retana, Rodrigo Landauro-Vera, Carlota Alvarez-Lucena, Marta Cascante and Lisardo Boscá
Molecules 2024, 29(2), 331; https://doi.org/10.3390/molecules29020331 - 09 Jan 2024
Viewed by 2500
Abstract
Trabectedin (TRB) and Lurbinectedin (LUR) are alkaloid compounds originally isolated from Ecteinascidia turbinata with proven antitumoral activity. Both molecules are structural analogues that differ on the tetrahydroisoquinoline moiety of the C subunit in TRB, which is replaced by a tetrahydro-β-carboline in LUR. TRB [...] Read more.
Trabectedin (TRB) and Lurbinectedin (LUR) are alkaloid compounds originally isolated from Ecteinascidia turbinata with proven antitumoral activity. Both molecules are structural analogues that differ on the tetrahydroisoquinoline moiety of the C subunit in TRB, which is replaced by a tetrahydro-β-carboline in LUR. TRB is indicated for patients with relapsed ovarian cancer in combination with pegylated liposomal doxorubicin, as well as for advanced soft tissue sarcoma in adults in monotherapy. LUR was approved by the FDA in 2020 to treat metastatic small cell lung cancer. Herein, we systematically summarise the origin and structure of TRB and LUR, as well as the molecular mechanisms that they trigger to induce cell death in tumoral cells and supporting stroma cells of the tumoral microenvironment, and how these compounds regulate immune cell function and fate. Finally, the novel therapeutic venues that are currently under exploration, in combination with a plethora of different immunotherapeutic strategies or specific molecular-targeted inhibitors, are reviewed, with particular emphasis on the usage of immune checkpoint inhibitors, or other bioactive molecules that have shown synergistic effects in terms of tumour regression and ablation. These approaches intend to tackle the complexity of managing cancer patients in the context of precision medicine and the application of tailor-made strategies aiming at the reduction of undesired side effects. Full article
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37 pages, 5829 KiB  
Review
Selenium—More than Just a Fortuitous Sulfur Substitute in Redox Biology
by Luisa B. Maia, Biplab K. Maiti, Isabel Moura and José J. G. Moura
Molecules 2024, 29(1), 120; https://doi.org/10.3390/molecules29010120 - 24 Dec 2023
Cited by 3 | Viewed by 1173
Abstract
Living organisms use selenium mainly in the form of selenocysteine in the active site of oxidoreductases. Here, selenium’s unique chemistry is believed to modulate the reaction mechanism and enhance the catalytic efficiency of specific enzymes in ways not achievable with a sulfur-containing cysteine. [...] Read more.
Living organisms use selenium mainly in the form of selenocysteine in the active site of oxidoreductases. Here, selenium’s unique chemistry is believed to modulate the reaction mechanism and enhance the catalytic efficiency of specific enzymes in ways not achievable with a sulfur-containing cysteine. However, despite the fact that selenium/sulfur have different physicochemical properties, several selenoproteins have fully functional cysteine-containing homologues and some organisms do not use selenocysteine at all. In this review, selected selenocysteine-containing proteins will be discussed to showcase both situations: (i) selenium as an obligatory element for the protein’s physiological function, and (ii) selenium presenting no clear advantage over sulfur (functional proteins with either selenium or sulfur). Selenium’s physiological roles in antioxidant defence (to maintain cellular redox status/hinder oxidative stress), hormone metabolism, DNA synthesis, and repair (maintain genetic stability) will be also highlighted, as well as selenium’s role in human health. Formate dehydrogenases, hydrogenases, glutathione peroxidases, thioredoxin reductases, and iodothyronine deiodinases will be herein featured. Full article
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35 pages, 1559 KiB  
Review
Mediterranean Shrub Species as a Source of Biomolecules against Neurodegenerative Diseases
by Natividad Chaves, Laura Nogales, Ismael Montero-Fernández, José Blanco-Salas and Juan Carlos Alías
Molecules 2023, 28(24), 8133; https://doi.org/10.3390/molecules28248133 - 16 Dec 2023
Viewed by 1904
Abstract
Neurodegenerative diseases are associated with oxidative stress, due to an imbalance in the oxidation-reduction reactions at the cellular level. Various treatments are available to treat these diseases, although they often do not cure them and have many adverse effects. Therefore, it is necessary [...] Read more.
Neurodegenerative diseases are associated with oxidative stress, due to an imbalance in the oxidation-reduction reactions at the cellular level. Various treatments are available to treat these diseases, although they often do not cure them and have many adverse effects. Therefore, it is necessary to find complementary and/or alternative drugs that replace current treatments with fewer side effects. It has been demonstrated that natural products derived from plants, specifically phenolic compounds, have a great capacity to suppress oxidative stress and neutralize free radicals thus, they may be used as alternative alternative pharmacological treatments for pathological conditions associated with an increase in oxidative stress. The plant species that dominate the Mediterranean ecosystems are characterized by having a wide variety of phenolic compound content. Therefore, these species might be important sources of neuroprotective biomolecules. To evaluate this potential, 24 typical plant species of the Mediterranean ecosystems were selected, identifying the most important compounds present in them. This set of plant species provides a total of 403 different compounds. Of these compounds, 35.7% are phenolic acids and 55.6% are flavonoids. The most relevant of these compounds are gallic, vanillic, caffeic, chlorogenic, p-coumaric, and ferulic acids, apigenin, kaempferol, myricitrin, quercetin, isoquercetin, quercetrin, rutin, catechin and epicatechin, which are widely distributed among the analyzed plant species (in over 10 species) and which have been involved in the literature in the prevention of different neurodegenerative pathologies. It is also important to mention that three of these plant species, Pistacea lentiscus, Lavandula stoechas and Thymus vulgaris, have most of the described compounds with protective properties against neurodegenerative diseases. The present work shows that the plant species that dominate the studied geographic area can provide an important source of phenolic compounds for the pharmacological and biotechnological industry to prepare extracts or isolated compounds for therapy against neurodegenerative diseases. Full article
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34 pages, 3299 KiB  
Review
Are There Lipid Membrane-Domain Subtypes in Neurons with Different Roles in Calcium Signaling?
by Alejandro K. Samhan-Arias, Joana Poejo, Dorinda Marques-da-Silva, Oscar H. Martínez-Costa and Carlos Gutierrez-Merino
Molecules 2023, 28(23), 7909; https://doi.org/10.3390/molecules28237909 - 02 Dec 2023
Cited by 3 | Viewed by 1875
Abstract
Lipid membrane nanodomains or lipid rafts are 10–200 nm diameter size cholesterol- and sphingolipid-enriched domains of the plasma membrane, gathering many proteins with different roles. Isolation and characterization of plasma membrane proteins by differential centrifugation and proteomic studies have revealed a remarkable diversity [...] Read more.
Lipid membrane nanodomains or lipid rafts are 10–200 nm diameter size cholesterol- and sphingolipid-enriched domains of the plasma membrane, gathering many proteins with different roles. Isolation and characterization of plasma membrane proteins by differential centrifugation and proteomic studies have revealed a remarkable diversity of proteins in these domains. The limited size of the lipid membrane nanodomain challenges the simple possibility that all of them can coexist within the same lipid membrane domain. As caveolin-1, flotillin isoforms and gangliosides are currently used as neuronal lipid membrane nanodomain markers, we first analyzed the structural features of these components forming nanodomains at the plasma membrane since they are relevant for building supramolecular complexes constituted by these molecular signatures. Among the proteins associated with neuronal lipid membrane nanodomains, there are a large number of proteins that play major roles in calcium signaling, such as ionotropic and metabotropic receptors for neurotransmitters, calcium channels, and calcium pumps. This review highlights a large variation between the calcium signaling proteins that have been reported to be associated with isolated caveolin-1 and flotillin-lipid membrane nanodomains. Since these calcium signaling proteins are scattered in different locations of the neuronal plasma membrane, i.e., in presynapses, postsynapses, axonal or dendritic trees, or in the neuronal soma, our analysis suggests that different lipid membrane-domain subtypes should exist in neurons. Furthermore, we conclude that classification of lipid membrane domains by their content in calcium signaling proteins sheds light on the roles of these domains for neuronal activities that are dependent upon the intracellular calcium concentration. Some examples described in this review include the synaptic and metabolic activity, secretion of neurotransmitters and neuromodulators, neuronal excitability (long-term potentiation and long-term depression), axonal and dendritic growth but also neuronal cell survival and death. Full article
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23 pages, 2324 KiB  
Review
Rafting on the Evidence for Lipid Raft-like Domains as Hubs Triggering Environmental Toxicants’ Cellular Effects
by Dorinda Marques-da-Silva and Ricardo Lagoa
Molecules 2023, 28(18), 6598; https://doi.org/10.3390/molecules28186598 - 13 Sep 2023
Cited by 2 | Viewed by 1843
Abstract
The plasma membrane lipid rafts are cholesterol- and sphingolipid-enriched domains that allow regularly distributed, sub-micro-sized structures englobing proteins to compartmentalize cellular processes. These membrane domains can be highly heterogeneous and dynamic, functioning as signal transduction platforms that amplify the local concentrations and signaling [...] Read more.
The plasma membrane lipid rafts are cholesterol- and sphingolipid-enriched domains that allow regularly distributed, sub-micro-sized structures englobing proteins to compartmentalize cellular processes. These membrane domains can be highly heterogeneous and dynamic, functioning as signal transduction platforms that amplify the local concentrations and signaling of individual components. Moreover, they participate in cell signaling routes that are known to be important targets of environmental toxicants affecting cell redox status and calcium homeostasis, immune regulation, and hormonal functions. In this work, the evidence that plasma membrane raft-like domains operate as hubs for toxicants’ cellular actions is discussed, and suggestions for future research are provided. Several studies address the insertion of pesticides and other organic pollutants into membranes, their accumulation in lipid rafts, or lipid rafts’ disruption by polychlorinated biphenyls (PCBs), benzo[a]pyrene (B[a]P), and even metals/metalloids. In hepatocytes, macrophages, or neurons, B[a]P, airborne particulate matter, and other toxicants caused rafts’ protein and lipid remodeling, oxidative changes, or amyloidogenesis. Different studies investigated the role of the invaginated lipid rafts present in endothelial cells in mediating the vascular inflammatory effects of PCBs. Furthermore, in vitro and in vivo data strongly implicate raft-localized NADPH oxidases, the aryl hydrocarbon receptor, caveolin-1, and protein kinases in the toxic mechanisms of occupational and environmental chemicals. Full article
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22 pages, 1310 KiB  
Review
Membrane Lipid Derivatives: Roles of Arachidonic Acid and Its Metabolites in Pancreatic Physiology and Pathophysiology
by Cándido Ortiz-Placín, Alba Castillejo-Rufo, Matías Estarás and Antonio González
Molecules 2023, 28(11), 4316; https://doi.org/10.3390/molecules28114316 - 24 May 2023
Viewed by 2090
Abstract
One of the most important constituents of the cell membrane is arachidonic acid. Lipids forming part of the cellular membrane can be metabolized in a variety of cellular types of the body by a family of enzymes termed phospholipases: phospholipase A2, phospholipase C [...] Read more.
One of the most important constituents of the cell membrane is arachidonic acid. Lipids forming part of the cellular membrane can be metabolized in a variety of cellular types of the body by a family of enzymes termed phospholipases: phospholipase A2, phospholipase C and phospholipase D. Phospholipase A2 is considered the most important enzyme type for the release of arachidonic acid. The latter is subsequently subjected to metabolization via different enzymes. Three enzymatic pathways, involving the enzymes cyclooxygenase, lipoxygenase and cytochrome P450, transform the lipid derivative into several bioactive compounds. Arachidonic acid itself plays a role as an intracellular signaling molecule. Additionally, its derivatives play critical roles in cell physiology and, moreover, are involved in the development of disease. Its metabolites comprise, predominantly, prostaglandins, thromboxanes, leukotrienes and hydroxyeicosatetraenoic acids. Their involvement in cellular responses leading to inflammation and/or cancer development is subject to intense study. This manuscript reviews the findings on the involvement of the membrane lipid derivative arachidonic acid and its metabolites in the development of pancreatitis, diabetes and/or pancreatic cancer. Full article
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