scholarly journals Multivalent interactions make adherens junction–cytoskeletal linkage robust during morphogenesis

2021 ◽  
Vol 220 (12) ◽  
Author(s):  
Kia Z. Perez-Vale ◽  
Kristi D. Yow ◽  
Ruth I. Johnson ◽  
Amy E. Byrnes ◽  
Tara M. Finegan ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Molecular Mechanisms ◽  
Adherens Junction ◽  
Large Protein ◽  
Epithelial Integrity ◽  
Network Nodes ◽  
Multidomain Protein ◽  
Multivalent Interactions ◽  
Actomyosin Cytoskeleton

Embryogenesis requires cells to change shape and move without disrupting epithelial integrity. This requires robust, responsive linkage between adherens junctions and the actomyosin cytoskeleton. Using Drosophila morphogenesis, we define molecular mechanisms mediating junction–cytoskeletal linkage and explore the role of mechanosensing. We focus on the junction–cytoskeletal linker Canoe, a multidomain protein. We engineered the canoe locus to define how its domains mediate its mechanism of action. To our surprise, the PDZ and FAB domains, which we thought connected junctions and F-actin, are not required for viability or mechanosensitive recruitment to junctions under tension. The FAB domain stabilizes junctions experiencing elevated force, but in its absence, most cells recover, suggesting redundant interactions. In contrast, the Rap1-binding RA domains are critical for all Cno functions and enrichment at junctions under tension. This supports a model in which junctional robustness derives from a large protein network assembled via multivalent interactions, with proteins at network nodes and some node connections more critical than others.

Molecular mechanisms of GABAB receptor activation: new insights from the mechanism of action of CGP7930, a positive allosteric modulator

2004 ◽  
Vol 32 (5) ◽  
pp. 871-872 ◽  
Author(s):  
V. Binet ◽  
C. Goudet ◽  
C. Brajon ◽  
L. Le Corre ◽  
F. Acher ◽  
...  
Keyword(s):  
G Protein ◽  
Mechanism Of Action ◽  
Molecular Mechanisms ◽  
Gabab Receptor ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Class Iii ◽  
G Protein Coupled ◽  
New Strategies

The GABAB (γ-aminobutyric acid-B) receptor is composed of two subunits, GABAB1 and GABAB2. Both subunits share structural homology with other class-III G-protein-coupled receptors. They contain two main domains, a heptahelical domain typical of all G-protein-coupled receptors and a large ECD (extracellular domain). It has not been demonstrated whether the association of these two subunits is always required for function. However, GABAB2 plays a major role in coupling with G-proteins, and GABAB1 has been shown to bind GABA. To date, only ligands interacting with GABAB1-ECD have been identified. In the present study, we explored the mechanism of action of CGP7930, a compound described as a positive allosteric regulator of the GABAB receptor. We have shown that it can weakly activate the wild-type GABAB receptor, but also the GABAB2 expressed alone, thus being the first described agonist of GABAB2. CGP7930 retains its weak agonist activity on a GABAB2 subunit deleted of its ECD. Thus the heptahelical domain of GABAB2 behaves similar to a rhodopsin-like receptor. These results open new strategies for studying the mechanism of activation of GABAB receptor and examine any possible role of GABAB2.

Multifarious Role of BAG3 in Neurodegenerative Disorders

2020 ◽  
pp. 261-281
Author(s):  
Sujata Basu ◽  
Manisha Singh ◽  
Mansi Verma ◽  
Rachana R.
Keyword(s):  
Nervous System ◽  
Glial Cells ◽  
Mechanism Of Action ◽  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Normal Development ◽  
Diagnostic Marker ◽  
The Body ◽  
Signaling Mechanism

The glial cells along with cells of hematopoietic origin and microvascular endothelia work together to maintain the normal development and/or functioning of the nervous system. Disruption in functional coordination among these cells interrupts the efficiency of the nervous system, leading to neurodegeneration. Various proteins in the nerve cells maintain the normal signaling mechanism with these cells and throughout the body. Structural/functional disorganization of these proteins causes neurodegenerative disorders. The molecular mechanisms involved in these phenomena are yet to be explored extensively from therapeutic perspectives. Through this chapter, the authors have elaborated on less known protein Bcl-2 associated athanogene 3 (BAG3) involved in neurodegeneration. They have explored BAG3 protein and its role in neurodegeneration, protein homeostasis, its mechanism of action, its uses as a drug target, and its uses as a possible diagnostic marker of neurodegeneration.

scholarly journals The Drosophila Afadin and ZO-1 homologues Canoe and Polychaetoid act in parallel to maintain epithelial integrity when challenged by adherens junction remodeling

2019 ◽  
Vol 30 (16) ◽  
pp. 1938-1960 ◽  
Author(s):  
Lathiena A. Manning ◽  
Kia Z. Perez-Vale ◽  
Kristina N. Schaefer ◽  
Mycah T. Sewell ◽  
Mark Peifer
Keyword(s):  
Cultured Cells ◽  
Adherens Junction ◽  
Leading Edge ◽  
Cell Junctions ◽  
Epithelial Integrity ◽  
Tissue Integrity ◽  
Mammalian Homologue ◽  
Cell Intercalation ◽  
Actomyosin Cytoskeleton ◽  
Cell Cell

During morphogenesis, cells must change shape and move without disrupting tissue integrity. This requires cell–cell junctions to allow dynamic remodeling while resisting forces generated by the actomyosin cytoskeleton. Multiple proteins play roles in junctional–cytoskeletal linkage, but the mechanisms by which they act remain unclear. Drosophila Canoe maintains adherens junction–cytoskeletal linkage during gastrulation. Canoe’s mammalian homologue Afadin plays similar roles in cultured cells, working in parallel with ZO-1 proteins, particularly at multicellular junctions. We take these insights back to the fly embryo, exploring how cells maintain epithelial integrity when challenged by adherens junction remodeling during germband extension and dorsal closure. We found that Canoe helps cells maintain junctional–cytoskeletal linkage when challenged by the junctional remodeling inherent in mitosis, cell intercalation, and neuroblast invagination or by forces generated by the actomyosin cable at the leading edge. However, even in the absence of Canoe, many cells retain epithelial integrity. This is explained by a parallel role played by the ZO-1 homologue Polychaetoid. In embryos lacking both Canoe and Polychaetoid, cell junctions fail early, with multicellular junctions especially sensitive, leading to widespread loss of epithelial integrity. Our data suggest that Canoe and Polychaetoid stabilize Bazooka/Par3 at cell–cell junctions, helping maintain balanced apical contractility and tissue integrity.

scholarly journals Concerted actions of distinct nonmuscle myosin II isoforms drive intracellular membrane remodeling in live animals

2017 ◽  
Vol 216 (7) ◽  
pp. 1925-1936 ◽  
Author(s):  
Oleg Milberg ◽  
Akiko Shitara ◽  
Seham Ebrahim ◽  
Andrius Masedunskas ◽  
Muhibullah Tora ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Secretory Granules ◽  
Myosin Ii ◽  
Membrane Remodeling ◽  
Nonmuscle Myosin ◽  
Nonmuscle Myosin Ii ◽  
Mammalian Tissues ◽  
Actomyosin Cytoskeleton

Membrane remodeling plays a fundamental role during a variety of biological events. However, the dynamics and the molecular mechanisms regulating this process within cells in mammalian tissues in situ remain largely unknown. In this study, we use intravital subcellular microscopy in live mice to study the role of the actomyosin cytoskeleton in driving the remodeling of membranes of large secretory granules, which are integrated into the plasma membrane during regulated exocytosis. We show that two isoforms of nonmuscle myosin II, NMIIA and NMIIB, control distinct steps of the integration process. Furthermore, we find that F-actin is not essential for the recruitment of NMII to the secretory granules but plays a key role in the assembly and activation of NMII into contractile filaments. Our data support a dual role for the actomyosin cytoskeleton in providing the mechanical forces required to remodel the lipid bilayer and serving as a scaffold to recruit key regulatory molecules.

scholarly journals Potential Cytoprotective Activity of Ozone Therapy in SARS-CoV-2/COVID-19

Antioxidants ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 389 ◽  
Author(s):  
Gregorio Martínez-Sánchez ◽  
Adriana Schwartz ◽  
Vincenzo Di Donna
Keyword(s):  
Mechanism Of Action ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Organ Damage ◽  
Experimental Models ◽  
Ozone Therapy ◽  
Cytoprotective Activity ◽  
Target Organs

(1) Background: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) in China at the end of 2019 has caused a large global outbreak. Systemic ozone therapy (OT) could be potentially useful in the clinical management of several complications secondary to SARS-CoV-2. The rationale and mechanism of action has already been proven clinically in other viral infections and has been shown in research studies to be highly effective at decreasing organ damage mediated by inflammation and oxidative stress. This review summarizes the OT studies that illustrate the possible cytoprotective mechanism of action of ozone and its physiological by-products in target organs affected by SARS-CoV-2. (2) Methods: This review encompasses a total of 74 peer-reviewed original articles. It is mainly focused on ozone as a modulator of the NF-κB/Nrf2 pathways and IL-6/IL-1β expression. (3) Results: In experimental models and the few existent clinical studies, homeostasis of the free radical and antioxidant balance by OT was associated with a modulation of NF-κB/Nrf2 balance and IL-6 and IL-1β expression. These molecular mechanisms support the cytoprotective effects of OT against tissue damage present in many inflammatory diseases, including viral infections. (4) Conclusions: The potential cytoprotective role of OT in the management of organ damage induced by COVID-19 merits further research. Controlled clinical trials are needed.

scholarly journals The Drosophila Afadin and ZO-1 homologs Canoe and Polychaetoid act in parallel to maintain epithelial integrity when challenged by adherens junction remodeling

2019 ◽  
Author(s):  
Lathiena A. Manning ◽  
Kia Z. Perez-Vale ◽  
Kristina N. Schaefer ◽  
Mycah T. Sewell ◽  
Mark Peifer
Keyword(s):  
Cultured Cells ◽  
Adherens Junction ◽  
Leading Edge ◽  
Cell Junctions ◽  
Dorsal Closure ◽  
Epithelial Integrity ◽  
Tissue Integrity ◽  
Cell Intercalation ◽  
Actomyosin Cytoskeleton ◽  
Cell Cell

AbstractDuring morphogenesis cells must change shape and move without disrupting tissue integrity. This requires cell-cell junctions to allow dynamic remodeling while resisting force generated by the actomyosin cytoskeleton. Multiple proteins play roles in junctional-cytoskeletal linkage, but the mechanisms by which they act remain unclear. Drosophila Canoe maintains adherens junction-cytoskeletal linkage during gastrulation. Canoe’s mammalian homolog Afadin plays similar roles in cultured cells, working in parallel with ZO-1 proteins, particularly at multicellular junctions. We took these insights back into the fly embryo, exploring how cells maintain epithelial integrity when challenged by adherens junction remodeling during germband extension and dorsal closure. We found Canoe helps cells maintain junctional-cytoskeletal linkage when challenged by the junctional remodeling inherent in mitosis, cell intercalation and neuroblast invagination, or by forces generated by the actomyosin cable at the leading edge. However, even in the absence of Canoe many cells retain epithelial integrity. This is explained by a parallel role played by the ZO-1 homolog Polychaetoid. In embryos lacking both Canoe and Polychaetoid, cell junctions fail early, with multicellular junctions especially sensitive, leading to widespread loss of epithelial integrity. Our data suggest Canoe and Polychaetoid stabilize Bazooka/Par3 at cell-cell junctions, helping maintain balanced apical contractility and tissue integrity.

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

Mesophyll conductance: the leaf corridors for photosynthesis

2020 ◽  
Vol 48 (2) ◽  
pp. 429-439 ◽  
Author(s):  
Jorge Gago ◽  
Danilo M. Daloso ◽  
Marc Carriquí ◽  
Miquel Nadal ◽  
Melanie Morales ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Main Role ◽  
Mesophyll Conductance ◽  
Future Studies ◽  
Cell Structures ◽  
Leaf Tissues ◽  
Change Framework ◽  
Chloroplast Stroma

Besides stomata, the photosynthetic CO2 pathway also involves the transport of CO2 from the sub-stomatal air spaces inside to the carboxylation sites in the chloroplast stroma, where Rubisco is located. This pathway is far to be a simple and direct way, formed by series of consecutive barriers that the CO2 should cross to be finally assimilated in photosynthesis, known as the mesophyll conductance (gm). Therefore, the gm reflects the pathway through different air, water and biophysical barriers within the leaf tissues and cell structures. Currently, it is known that gm can impose the same level of limitation (or even higher depending of the conditions) to photosynthesis than the wider known stomata or biochemistry. In this mini-review, we are focused on each of the gm determinants to summarize the current knowledge on the mechanisms driving gm from anatomical to metabolic and biochemical perspectives. Special attention deserve the latest studies demonstrating the importance of the molecular mechanisms driving anatomical traits as cell wall and the chloroplast surface exposed to the mesophyll airspaces (Sc/S) that significantly constrain gm. However, even considering these recent discoveries, still is poorly understood the mechanisms about signaling pathways linking the environment a/biotic stressors with gm responses. Thus, considering the main role of gm as a major driver of the CO2 availability at the carboxylation sites, future studies into these aspects will help us to understand photosynthesis responses in a global change framework.

SOME ASPECTS OF THE FUNCTION OF FSH- AND LH-LIKE HORMONES IN NORMAL AND HYPOPHYSECTOMIZED FEMALE RATS, IN CONNECTION WITH RESERPINE ADMINISTRATION

1965 ◽  
Vol 49 (1) ◽  
pp. 28-38
Author(s):  
M. Grönroos ◽  
E. Mäkinen ◽  
K. Lahtinen ◽  
R. Tirri
Keyword(s):  
Mechanism Of Action ◽  
Biological Effect ◽  
Female Rats ◽  
Histological Picture ◽  
Peripheral Effect ◽  
Pituitary Secretion

ABSTRACT The effect of reserpine on the secretion of FSH and LH was studied as well as the role of the peripheral effect of reserpine after hypophysectomy. The results in the unoperated animals suggest that reserpine inhibits the pituitary secretion of both FSH and LH. Both these hormones combined with reserpine had a very different biological effect than was seen without reserpine. HCG (LH-like) and particularly PMS (FSH-like) hormones combined with reserpine caused definite enlargement of the ovaries. In the hypophysectomized groups, the effect of the PMS and HCG hormones administered together with reserpine or without it was the same with regard to the weight of the ovaries, but not with regard to their histological picture. On the basis of these results, reserpine may be said to have a peripheral effect although the nature of its mechanism of action is difficult to state. Reserpine probably affects the ovaries by inhibiting the follicular cycle and, consequently, the formation of new and more mature follicles.

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