scholarly journals Membrane-associated α-tubulin is less acetylated in postmortem prefrontal cortex from depressed subjects relative to controls: cytoskeletal dynamics, HDAC6 and depression

2020 ◽  
Author(s):  
Harinder Singh ◽  
Justyna Chmura ◽  
Runa Bhaumik ◽  
Ghanshyam N. Pandey ◽  
Mark M. Rasenick
Keyword(s):  
Plasma Membrane ◽  
Adenylyl Cyclase ◽  
Mood Disorders ◽  
Lipid Raft ◽  
Antidepressant Treatment ◽  
Tissue Homogenate ◽  
Post Translational Modifications ◽  
Tubulin Acetylation ◽  
Raft Domains ◽  
Membrane Tubulin

AbstractCytoskeletal proteins and post-translational modifications play a role in mood disorders. Post-translational modifications of tubulin also alter microtubule dynamics. Furthermore, tubulin interacts closely with Gαs, the G-protein responsible for activation of adenylyl cyclase. Postmortem tissue derived from depressed suicide brain showed increased Gαs in lipid-raft domains compared to normal subjects. Gαs, when ensconced in lipid-rafts, couples less effectively with adenylyl cyclase to produce cAMP and this is reversed by antidepressant treatment. A recent in-vitro study demonstrated that tubulin anchors Gαs to lipid-rafts and that increased tubulin acetylation (due to HDAC-6 inhibition) and antidepressant treatment decreased the proportion of Gαs complexed with tubulin. This suggested that deacetylated-tubulin might be more prevalent in depression. This study, examined tubulin acetylation in whole tissue homogenate, plasma-membrane and lipid-raft membrane domains in tissue from normal control (NC) subjects, depressed suicides and depressed non-suicides. While tissue homogenate showed no changes in 〈-tubulin/tubulin acetylation between control, depressed suicides and depressed non-suicides, plasma-membrane associated tubulin showed significant decreases in acetylation in depressed suicides and depressed non-suicides compared to controls. No change was seen in expression of the enzymes responsible for tubulin acetylation or deacetylation. These data suggest that during depression, membrane localized tubulin maintains a lower acetylation state, permitting increased sequestration of Gαs in lipid-raft domains, where it is less likely to couple to adenylyl cyclase for cAMP production. Thus, membrane tubulin may play a role in mood disorders which could be exploited for diagnosis and treatment.Significance StatementThere is little understanding about the molecular mechanisms involved in the development of depression and in severe cases, suicide. Evidence for the role of microtubule modifications in progression of depressive disorders is emerging. These postmortem data provide strong evidence for membrane tubulin modification leading to reduced efficacy of the G protein, Gsα, in depression. This study reveals a direct link between decreased tubulin acetylation in human depression and the increased localization of Gαs in lipid-raft domains responsible for attenuated cAMP signaling. The evidence presented here suggest a novel diagnostic and therapeutic locus for depression.

scholarly journals Compartmentalization of the Exocyst Complex in Lipid Rafts Controls Glut4 Vesicle Tethering

2006 ◽  
Vol 17 (5) ◽  
pp. 2303-2311 ◽  
Author(s):  
Mayumi Inoue ◽  
Shian-Huey Chiang ◽  
Louise Chang ◽  
Xiao-Wei Chen ◽  
Alan R. Saltiel
Keyword(s):  
Plasma Membrane ◽  
Glucose Uptake ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Pdz Domain ◽  
Vesicle Tethering ◽  
Exocyst Complex ◽  
Raft Domains ◽  
Lipid Raft Microdomains ◽  
Stimulation Of

Lipid raft microdomains act as organizing centers for signal transduction. We report here that the exocyst complex, consisting of Exo70, Sec6, and Sec8, regulates the compartmentalization of Glut4-containing vesicles at lipid raft domains in adipocytes. Exo70 is recruited by the G protein TC10 after activation by insulin and brings with it Sec6 and Sec8. Knockdowns of these proteins block insulin-stimulated glucose uptake. Moreover, their targeting to lipid rafts is required for glucose uptake and Glut4 docking at the plasma membrane. The assembly of this complex also requires the PDZ domain protein SAP97, a member of the MAGUKs family, which binds to Sec8 upon its translocation to the lipid raft. Exocyst assembly at lipid rafts sets up targeting sites for Glut4 vesicles, which transiently associate with these microdomains upon stimulation of cells with insulin. These results suggest that the TC10/exocyst complex/SAP97 axis plays an important role in the tethering of Glut4 vesicles to the plasma membrane in adipocytes.

scholarly journals The Antipsychotic Risperidone Alters Dihydroceramide and Ceramide Composition and Plasma Membrane Function in Leukocytes In Vitro and In Vivo

2021 ◽  
Vol 22 (8) ◽  
pp. 3919
Author(s):  
Alberto Canfrán-Duque ◽  
Óscar Pastor ◽  
David García-Seisdedos ◽  
Yessenia L. Molina ◽  
Bohdan Babiy ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Lipid Raft ◽  
Older Patients ◽  
In Vitro Assays ◽  
Fatty Acid Elongase ◽  
Membrane Function ◽  
Increased Risk ◽  
Raft Domains ◽  
Long Chain

Atypical or second-generation antipsychotics are used in the treatment of psychosis and behavioral problems in older persons with dementia. However, these pharmaceutical drugs are associated with an increased risk of stroke in such patients. In this study, we evaluated the effects of risperidone treatment on phospholipid and sphingolipid composition and lipid raft function in peripheral blood mononuclear cells (PBMCs) of older patients (mean age >88 years). The results showed that the levels of dihydroceramides, very-long-chain ceramides, and lysophosphatidylcholines decreased in PBMCs of the risperidone-treated group compared with untreated controls. These findings were confirmed by in vitro assays using human THP-1 monocytes. The reduction in the levels of very-long-chain ceramides and dihydroceramides could be due to the decrease in the expression of fatty acid elongase 3, as observed in THP-1 monocytes. Moreover, risperidone disrupted lipid raft domains in the plasma membrane of PBMCs. These results indicated that risperidone alters phospholipid and sphingolipid composition and lipid raft domains in PBMCs of older patients, potentially affecting multiple signaling pathways associated with these membrane domains.

scholarly journals Lipid Rafts Are Triage Centers for Multimeric and Monomeric Thyrotropin Receptor Regulation

Endocrinology ◽  
2007 ◽  
Vol 148 (7) ◽  
pp. 3164-3175 ◽  
Author(s):  
R. Latif ◽  
T. Ando ◽  
T. F. Davies
Keyword(s):  
Plasma Membrane ◽  
G Protein ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Significant Proportion ◽  
Lipid Microdomains ◽  
Biochemical Approach ◽  
Biochemical Analyses ◽  
Raft Domains ◽  
G Protein Coupled

The TSH receptor (TSHR), a heptahelical G protein-coupled receptor on the surface of thyrocytes, is a major autoantigen and physiological regulator of the thyroid gland. Unlike other G protein-coupled receptors, the TSHR undergoes posttranslational cleavage of its ectodomain, leading to the existence of several forms of the receptor on the plasma membrane. We previously hypothesized that to achieve high fidelity and specificity of TSH ligand or TSHR autoantibody signaling, the TSHR may compartmentalize into microdomains within the plasma membrane. In support of this hypothesis we have shown previously that TSHRs reside in GM1 ganglioside-enriched lipid rafts in the plasma membrane of TSHR-expressing cells. In this study, we further explored the different forms of TSHRs that reside in lipid rafts. We studied both TSHR-transfected cells and rat thyrocytes, using both nondetergent biochemical analyses and receptor-lipid raft colocalization. Using the biochemical approach, we observed that monomeric receptors existed in both raft and nonraft fractions of the cell surface in the steady state. We also demonstrated that the multimeric forms of the receptor were preferentially partitioned into the lipid microdomains. Different TSHR forms, including multimers, were dynamically regulated both by receptor-specific and postreceptor-specific modulators. TSH ligand and TSHR antibody of the stimulating variety induced a decrease of multimeric forms in the raft fractions. In addition, multimeric and monomeric forms of the receptor were both associated with Gsα within and without the rafts. Although failure to achieve total lipid raft disruption prevented a conclusion regarding the relative power of TSHR signaling within and without the raft domains, these data showed clearly that not only were a significant proportion of TSHRs residing within lipid microdomains but that constitutive multimerization of TSHRs was actually regulated within the lipid rafts.

scholarly journals Lattices, rafts, and scaffolds: domain regulation of receptor signaling at the plasma membrane

2009 ◽  
Vol 185 (3) ◽  
pp. 381-385 ◽  
Author(s):  
Patrick Lajoie ◽  
Jacky G. Goetz ◽  
James W. Dennis ◽  
Ivan R. Nabi
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Lipid Raft ◽  
Scaffold Proteins ◽  
Cell Junctions ◽  
Cross Link ◽  
Coated Pits ◽  
Receptor Dynamics ◽  
Raft Domains ◽  
Molecular Lattices

The plasma membrane is organized into various subdomains of clustered macromolecules. Such domains include adhesive structures (cellular synapses, substrate adhesions, and cell–cell junctions) and membrane invaginations (clathrin-coated pits and caveolae), as well as less well-defined domains such as lipid rafts and lectin-glycoprotein lattices. Domains are organized by specialized scaffold proteins including the intramembranous caveolins, which stabilize lipid raft domains, and the galectins, a family of animal lectins that cross-link glycoproteins forming molecular lattices. We review evidence that these heterogeneous microdomains interact to regulate substratum adhesion and cytokine receptor dynamics at the cell surface.

Caveolin-1, galectin-3 and lipid raft domains in cancer cell signalling

2015 ◽  
Vol 57 ◽  
pp. 189-201 ◽  
Author(s):  
Jay Shankar ◽  
Cecile Boscher ◽  
Ivan R. Nabi
Keyword(s):  
Plasma Membrane ◽  
Lipid Rafts ◽  
Cancer Cell ◽  
Cellular Response ◽  
Spatial Organization ◽  
Essential Feature ◽  
Cell Signalling ◽  
Coated Pits ◽  
Signalling Molecules ◽  
Raft Domains

Spatial organization of the plasma membrane is an essential feature of the cellular response to external stimuli. Receptor organization at the cell surface mediates transmission of extracellular stimuli to intracellular signalling molecules and effectors that impact various cellular processes including cell differentiation, metabolism, growth, migration and apoptosis. Membrane domains include morphologically distinct plasma membrane invaginations such as clathrin-coated pits and caveolae, but also less well-defined domains such as lipid rafts and the galectin lattice. In the present chapter, we will discuss interaction between caveolae, lipid rafts and the galectin lattice in the control of cancer cell signalling.

scholarly journals Cannabinoid receptors distribution in mouse cortical plasma membrane compartments

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Hajar Miranzadeh Mahabadi ◽  
Haseeb Bhatti ◽  
Robert B. Laprairie ◽  
Changiz Taghibiglou
Keyword(s):  
Plasma Membrane ◽  
Lipid Raft ◽  
Cannabinoid Receptors ◽  
Gradient Centrifugation ◽  
Brain Regions ◽  
Cb1 Receptor ◽  
The Body ◽  
Cb2 Receptor ◽  
Cortical Tissue ◽  
Ionic Detergent

AbstractThe type 1 and type 2 cannabinoid receptors (CB1 and CB2 receptors) are class A G protein-coupled receptors (GPCRs) that are activated by endogenous lipids called endocannabinoids to modulate neuronal excitability and synaptic transmission in neurons throughout the central nervous system (CNS), and inflammatory processes throughout the body. CB1 receptor is one of the most abundant GPCRs in the CNS and is involved in many physiological and pathophysiological processes, including mood, appetite, and nociception. CB2 receptor is primarily found on immunomodulatory cells of both the CNS and the peripheral immune system. In this study, we isolated lipid raft and non-lipid raft fractions of plasma membrane (PM) from mouse cortical tissue by using cold non-ionic detergent and sucrose gradient centrifugation to study the localization of CB1 receptor and CB2 receptor. Lipid raft and non-lipid raft fractions were confirmed by flotillin-1, caveolin-1 and transferrin receptor as their protein biomarkers. Both CB1 receptor and CB2 receptor were found in non-raft compartments that is inconsistent with previous findings in cultured cell lines. This study demonstrates compartmentalization of both CB1 receptor and CB2 receptor in cortical tissue and warrants further investigation of CB1 receptor and CB2 receptor compartmental distribution in various brain regions and cell types.

scholarly journals RalA and RalB Proteins Are Ubiquitinated GTPases, and Ubiquitinated RalA Increases Lipid Raft Exposure at the Plasma Membrane

2012 ◽  
Vol 287 (35) ◽  
pp. 29397-29405 ◽  
Author(s):  
Vincent Neyraud ◽  
Vasily N. Aushev ◽  
Anastassia Hatzoglou ◽  
Brigitte Meunier ◽  
Ilaria Cascone ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Lipid Raft
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