scholarly journals Hydrocephalus: the role of cerebral aquaporin-4 channels and computational modeling considerations of cerebrospinal fluid

2016 ◽  
Vol 41 (3) ◽  
pp. E8 ◽  
Author(s):  
Bhargav Desai ◽  
Ying Hsu ◽  
Benjamin Schneller ◽  
Jonathan G. Hobbs ◽  
Ankit I. Mehta ◽  
...  
Keyword(s):  
Computational Modeling ◽  
Plasma Membranes ◽  
Water Exchange ◽  
Critical Role ◽  
Disease Process ◽  
Aquaporin 4 ◽  
Fluid Exchange ◽  
Pharmaceutical Therapy ◽  
Molecular Aspects ◽  
Brain Water

Aquaporin-4 (AQP4) channels play an important role in brain water homeostasis. Water transport across plasma membranes has a critical role in brain water exchange of the normal and the diseased brain. AQP4 channels are implicated in the pathophysiology of hydrocephalus, a disease of water imbalance that leads to CSF accumulation in the ventricular system. Many molecular aspects of fluid exchange during hydrocephalus have yet to be firmly elucidated, but review of the literature suggests that modulation of AQP4 channel activity is a potentially attractive future pharmaceutical therapy. Drug therapy targeting AQP channels may enable control over water exchange to remove excess CSF through a molecular intervention instead of by mechanical shunting. This article is a review of a vast body of literature on the current understanding of AQP4 channels in relation to hydrocephalus, details regarding molecular aspects of AQP4 channels, possible drug development strategies, and limitations. Advances in medical imaging and computational modeling of CSF dynamics in the setting of hydrocephalus are summarized. Algorithmic developments in computational modeling continue to deepen the understanding of the hydrocephalus disease process and display promising potential benefit as a tool for physicians to evaluate patients with hydrocephalus.

scholarly journals Cerebral Microcirculation, Perivascular Unit, and Glymphatic System: Role of Aquaporin-4 as the Gatekeeper for Water Homeostasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jacek Szczygielski ◽  
Marta Kopańska ◽  
Anna Wysocka ◽  
Joachim Oertel
Keyword(s):  
Water Exchange ◽  
Aquaporin 4 ◽  
Cerebral Microcirculation ◽  
Fluid Exchange ◽  
Intracellular Space ◽  
Glymphatic System ◽  
Water Homeostasis ◽  
Fluid Homeostasis ◽  
New Concepts

In the past, water homeostasis of the brain was understood as a certain quantitative equilibrium of water content between intravascular, interstitial, and intracellular spaces governed mostly by hydrostatic effects i.e., strictly by physical laws. The recent achievements in molecular bioscience have led to substantial changes in this regard. Some new concepts elaborate the idea that all compartments involved in cerebral fluid homeostasis create a functional continuum with an active and precise regulation of fluid exchange between them rather than only serving as separate fluid receptacles with mere passive diffusion mechanisms, based on hydrostatic pressure. According to these concepts, aquaporin-4 (AQP4) plays the central role in cerebral fluid homeostasis, acting as a water channel protein. The AQP4 not only enables water permeability through the blood-brain barrier but also regulates water exchange between perivascular spaces and the rest of the glymphatic system, described as pan-cerebral fluid pathway interlacing macroscopic cerebrospinal fluid (CSF) spaces with the interstitial fluid of brain tissue. With regards to this, AQP4 makes water shift strongly dependent on active processes including changes in cerebral microcirculation and autoregulation of brain vessels capacity. In this paper, the role of the AQP4 as the gatekeeper, regulating the water exchange between intracellular space, glymphatic system (including the so-called neurovascular units), and intravascular compartment is reviewed. In addition, the new concepts of brain edema as a misbalance in water homeostasis are critically appraised based on the newly described role of AQP4 for fluid permeation. Finally, the relevance of these hypotheses for clinical conditions (including brain trauma and stroke) and for both new and old therapy concepts are analyzed.

Abstract 629: Differential Expression Of Angiotensin-(1-12)/chymase In Human Atrial Tissue

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Sayaka Nagata ◽  
Jasmina Varagic ◽  
Stephen W Simington ◽  
Sarfraza Ahmad ◽  
Jessica L VonCannon ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Heart Surgery ◽  
Critical Role ◽  
Disease Process ◽  
The Novel ◽  
Ang Ii ◽  
Atrial Tissue ◽  
Right Atria ◽  
Tissues Expression

Proangiotensin-12 [Ang-(1-12)] is a C-terminal extended form of Ang I [Ang I-Leu-Tyr] originally isolated from the rat small intestine. Additional studies showed that while both ACE and chymase cleaved Ang II from Ang-(1-12) in the rat heart, chymase but not ACE metabolized Ang-(1-12) in the human heart. This study characterized the expression of Ang-(1-12)/chymase in human atrial tissue to gain an insight into the potential role of this Ang II-forming substrate in cardiac disease. Left (LA; n=16) and right (RA; n=14) portions of atrial appendages were obtained from humans undergoing heart surgery. Quantitative Ang-(1-12) immunohistochemistry (Image J software) was performed using a high affinity purified antibody directed to the COOH-terminus of the full length of human Ang-(1-12) in all samples (LA: male=13 and female=3; RA: male=9 and female=5). Chymase activity was determined by HPLC in plasma membranes from left (males=7 and females=3) and right atria (males=7 and females=3). Quantitative analysis of Ang-(1-12) expression revealed significantly higher Ang-(1-12) expression in LA (Intensity: 35.37±6.24 units) versus RA (19.38±2.38 units, p=0.03) appendages. Likewise, chymase activity was higher in the LA (52.02±5.20 fmol/mg/min) compared to RA (18.09±3.05, p<0.0001) tissues. Expression of Ang-(1-12) in atria did not correlate with subject’s age, disease process or medications. The novel demonstration of higher Ang-(1-12) expression and chymase activity in human LA reveals a critical role of this tissue Ang II forming axis in modulating the diastolic and systolic properties of this cardiac cavity.

scholarly journals Increased cerebral vascularization and decreased water exchange across the blood-brain barrier in aquaporin-4 knockout mice

PLoS ONE ◽  
2019 ◽  
Vol 14 (6) ◽  
pp. e0218415 ◽  
Author(s):  
Yifan Zhang ◽  
Kui Xu ◽  
Yuchi Liu ◽  
Bernadette O. Erokwu ◽  
Pan Zhao ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Knockout Mice ◽  
Water Exchange ◽  
Aquaporin 4 ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Molecular Determinants of μ-Conotoxin KIIIA Interaction with the Voltage-Gated Sodium Channel Nav1.7

2019 ◽  
Author(s):  
Ian H. Kimball ◽  
Phuong T. Nguyen ◽  
Baldomero M. Olivera ◽  
Jon T. Sack ◽  
Vladimir Yarov-Yarovoy
Keyword(s):  
Computational Modeling ◽  
Rational Design ◽  
Structural Model ◽  
Critical Role ◽  
Structural Data ◽  
Molecular Probes ◽  
Integrative Approach ◽  
In Silico Docking ◽  
Voltage Gated ◽  
Dynamics Simulations

AbstractThe voltage-gated sodium (Nav) channel subtype Nav1.7 plays a critical role in pain signaling, making it an important drug target. Here we studied the molecular interactions between μ-conotoxin KIIIA (KIIIA) and the human Nav1.7 channel (hNav1.7). We developed a structural model of hNav1.7 using Rosetta computational modeling and performed in silico docking of KIIIA using RosettaDock to predict residues forming specific pairwise contacts between KIIIA and hNav1.7. We experimentally validated these contacts using mutant cycle analysis. Comparison between our KIIIA-hNav1.7 model and the recently published cryo-EM structure of KIIIA-hNav1.2 revealed key similarities and differences between channel subtypes with potential implications for the molecular mechanism of toxin block. Our integrative approach, combining structural data with computational modeling, experimental validation, and molecular dynamics simulations will be useful for engineering molecular probes to study Nav channel function, and for rational design of novel biologics targeting specific Nav channels.

Cobalamin transport proteins and their cell-surface receptors

2003 ◽  
Vol 5 (18) ◽  
pp. 1-18 ◽  
Author(s):  
Bellur Seetharam ◽  
Raghunatha R. Yammani
Keyword(s):  
Cell Surface ◽  
Blood Cells ◽  
Plasma Membranes ◽  
Intrinsic Factor ◽  
Transport Proteins ◽  
Cell Surface Receptors ◽  
Vitamin B ◽  
Cellular Transport ◽  
Surface Receptors ◽  
Molecular Aspects

The primary function of cobalamin (Cbl; vitamin B12) is the formation of red blood cells and the maintenance of a healthy nervous system. Before cells can utilise dietary Cbl, the vitamin must undergo cellular transport using two distinct receptor-mediated events. First, dietary Cbl bound to gastric intrinsic factor (IF) is taken up from the apical pole of ileal epithelial cells via a 460 kDa receptor, cubilin, and is transported across the cell bound to another Cbl-binding protein, transcobalamin II (TC II). Second, plasma TC II–Cbl is taken up by cells that need Cbl via the TC II receptor (TC II-R), a 62 kDa protein that is expressed as a functional dimer in cellular plasma membranes. Human Cbl deficiency can develop as a result of acquired or inherited dysfunction in either of these two transmembrane transport events. This review focuses on the biochemical, cellular and molecular aspects of IF and TC II and their cell-surface receptors.

Inflammatory cell recruitment in cardiovascular disease: murine models and potential clinical applications

2010 ◽  
Vol 118 (11) ◽  
pp. 641-655 ◽  
Author(s):  
Eileen McNeill ◽  
Keith M. Channon ◽  
David R. Greaves
Keyword(s):  
Cardiovascular Disease ◽  
Atherosclerotic Plaque ◽  
Critical Role ◽  
Disease Process ◽  
Pathological Process ◽  
Plaque Formation ◽  
Murine Models ◽  
Subsequent Transformation ◽  
Inflammatory Monocytes ◽  
Atherosclerotic Plaque Formation

Atherosclerosis is the pathological process that underlies the development of cardiovascular disease, a leading cause of mortality. Atherosclerotic plaque formation is driven by the recruitment of inflammatory monocytes into the artery wall, their differentiation into macrophages and the subsequent transformation of macrophages into cholesterol-laden foam cells. Models of hypercholesterolaemia such as the ApoE (apolipoprotein E)−/− mouse and the application of transgenic technologies have allowed us to undertake a thorough dissection of the cellular and molecular biology of the atherosclerotic disease process. Murine models have emphasized the central role of inflammation in atherogenesis and have been instrumental in the identification of adhesion molecules that support monocyte recruitment, scavenger receptors that facilitate cholesterol uptake by macrophages and other macrophage activation receptors. The study of mice deficient in multiple members of the chemokine family, and their receptors, has shown that chemokines play a critical role in promoting atherosclerotic plaque formation. In the present review, we will discuss novel therapeutic avenues for the treatment of cardiovascular disease that derive directly from our current understanding of atherogenesis gained in experimental animal models.

scholarly journals The critical role of lipopolysaccharide in the upregulation of aquaporin 4 in glial cells treated with Shiga toxin

2015 ◽  
Vol 22 (1) ◽  
Author(s):  
Naotoshi Sugimoto ◽  
Hue Leu ◽  
Natsumi Inoue ◽  
Masaki Shimizu ◽  
Tomoko Toma ◽  
...  
Keyword(s):  
Glial Cells ◽  
Shiga Toxin ◽  
Critical Role ◽  
Aquaporin 4

scholarly journals The Ras Target AF-6 is a Substrate of the Fam Deubiquitinating Enzyme

1998 ◽  
Vol 142 (4) ◽  
pp. 1053-1062 ◽  
Author(s):  
Shinichiro Taya ◽  
Takaharu Yamamoto ◽  
Kyoko Kano ◽  
Yoji Kawano ◽  
Akihiro Iwamatsu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Plasma Membranes ◽  
Critical Role ◽  
Amino Acid Sequences ◽  
Cell Contact ◽  
Deubiquitinating Enzyme ◽  
Intact Cells ◽  
Cell Adhesions ◽  
Fat Facets ◽  
Cell Cell

The Ras target AF-6 has been shown to serve as one of the peripheral components of cell–cell adhesions, and is thought to participate in cell–cell adhesion regulation downstream of Ras. We here purified an AF-6-interacting protein with a molecular mass of ∼220 kD (p220) to investigate the function of AF-6 at cell–cell adhesions. The peptide sequences of p220 were identical to the amino acid sequences of mouse Fam. Fam is homologous to a deubiquitinating enzyme in Drosophila, the product of the fat facets gene. Recent genetic analyses indicate that the deubiquitinating activity of the fat facets product plays a critical role in controlling the cell fate. We found that Fam accumulated at the cell–cell contact sites of MDCKII cells, but not at free ends of plasma membranes. Fam was partially colocalized with AF-6 and interacted with AF-6 in vivo and in vitro. We also showed that AF-6 was ubiquitinated in intact cells, and that Fam prevented the ubiquitination of AF-6.

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