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Specific Host Restance: The Effector Mechanisms
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
The fragment on the membranes of cells serves as the initiating point for the assembly of the remaining complement components, C6 through C9, into a structure termed the membrane attack complex (MAC). The assembly of the complex occurs in several steps. The fragments bind C6, C7, and C8. C7 and C8 undergo conformational changes exposing hydrophobic regions that embed into the cell membrane. The complex serves as a nucleation point that brings about the polymerization of up to sixteen C9 molecules. The polymerized C9 molecules form a cylindrical tubule that inserts into the cell membrane making a hole. This transmembrane channel permits water and ions to flow into the cell. As a consequence the cell swells and bursts. Before bursting, the proton gradient used by a bacterium to generate ATP is also destroyed. Nucleated cells often simply lose their cytoplasm through the pores rather than swelling and bursting (Figure 9.4).
A Biophysical View on the Function and Activity of Endotoxins
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Ulrich Seydel, Andre Wiese, Andra B. Schromm, Klaus Brandenburg
For these functions to work properly, a particular lipid composition on each side and distribution between both sides of the lipid bilayer are required. Thus, a membrane is built up from a large variety of lipids, differing in charge and fatty acid substitution (length and degree of saturation), and these lipids are in a delicate equilibrium providing a suitable environment for protein function and membrane permeability. By a complex interaction of passive and active transport processes (diffusion through the lipid matrix or protein-aligned transmembrane channels and by energy-dependent ion pumps and transport proteins, respectively) ion gradients are built up that contribute, together with the charge distribution of the lipids on the two leaflets of the membrane, to a transmembrane potential.
Design of Nerve-to-Muscle Information Systems
Published in Peter W. Hochachka, Muscles as Molecular and Metabolic Machines, 2019
In Chapter 2, we noted that the transduction of nerve impulses into muscle contraction depends upon an information flow from motor nerve terminals, across an extracellular gap (the synapse) to the end plate, across the muscle cell surface, down the transverse tubules, and finally across an intracellular gap (between TT and SR) to the SR, which releases enough Ca++ to initiate contraction. Thus, the signal must cross (minimally) five membrane barriers and two potentially diffusion-limited gaps (one, the synapse, being extracellular, the other the intracellular gap between the TT, the SR, and the contractile elements). For these processes, at least six ion-selective transmembrane channels are required in vertebrate skeletal muscles (seven in cardiac muscle, since here a surface Ca++ channel isoform plays a significant role in excitation-contraction coupling). If this system were simply maximized for speed, direct electrical synapses would obviously be the signal transduction mechanism of choice, as indeed is found in fast synapses in some invertebrates. Vertebrates did not take this route, we assume because of a trade-off of regulation for speed; i.e., what seems to be selected for is a signal transmission system that is optimized for regulated high speed function. We have already discussed some of the regulating mechanisms known. What about speed? Since the fundamental signal transmission system depends so critically on channels, the question can be rephrased in a more general way: How fast can channels work?
The therapeutic prospect of zinc oxide nanoparticles in experimentally induced diabetic nephropathy
Published in Tissue Barriers, 2023
Samia A. Abd El-Baset, Nehad F. Mazen, Rehab S. Abdul-Maksoud, Asmaa A. A. Kattaia
Aquaporins (AQPs), transmembrane channels, selectively transport water and some solutes across the cell. AQPs include 13 members (AQP0–AQP12), eight of them (AQP1–AQP7 and AQP11) are distributed in different parts of the kidney47, 48. AQP11 is mainly expressed in the proximal tubules, associated with the endoplasmic reticulum, and controlled by glucose. AQP11 plays an important role in the homeostasis of endoplasmic reticulum and in maintaining the osmolality of cytosol and vesicles. A recessive mutation in mouse AQP11 (Cysteine 227 to Serine 227) resulted in damage of the proximal tubules and renal failure in mutant animals.11 In the present work, there was statistically significant reduction in AQP11 immune histochemical expression in the diabetic group when compared to the controls. AQP11 inadequacy disposes to diabetic kidney disease and hyperglycemia-stimulated renal dysfunction.49 Previously, diabetic polyuria was believed to result from osmotic diuresis due to hyperglycemia. Later, it was found that polyuria is caused by AQPs disorders.50
Cell-cell junctions: structure and regulation in physiology and pathology
Published in Tissue Barriers, 2021
Mir S. Adil, S. Priya Narayanan, Payaningal R. Somanath
It is a fundamental property of transmembrane channels at the molecular level. This establishes a mechanism by which channel permeability can be regulated by voltage, extracellular ligands, and intracellular or intramembrane signals. It is still unknown whether paracellular CLDN pores also exhibit gating.77 The initial hypothesis is that TJ strands seldom exhibit breaks through which macromolecules can diffuse from TJ mesh to TJ mesh and then reseal, without the compulsion to permanently open up a large gap across the entire TJ system. Another hypothesis is that the leak takes place at the tricellular junction. This is centered on the observation that moderate overexpression of tricellulin specifically lowers paracellular permeability to macromolecules, but not to small inorganic ions. Under these conditions, tricellulin exhibits a strictly tricellular distribution.77
Binding affinity in drug design: experimental and computational techniques
Published in Expert Opinion on Drug Discovery, 2019
Visvaldas Kairys, Lina Baranauskiene, Migle Kazlauskiene, Daumantas Matulis, Egidijus Kazlauskas
It is possible to obtain accurate distance vs. free energy profiles from a molecular dynamics calculation analyzing the thermally driven (i.e. Poisson-Boltzmann) distribution of the distances during the simulation [99]. Unfortunately, the system itself can easily become too big to traverse the conformational space during the limited time available for the calculation. In addition, the potential energy barriers could be too high to be surmounted during MD: for example, the ligand-protein complex is often likely to stay bound during the simulation. This can be overcome by enhanced sampling techniques [100,101]. One of such techniques is called umbrella sampling [100]. In this method, the whole reaction path (for example, dissociation/association coordinate of a complex) is split into a series of windows, and a harmonic bias is imposed for each window. The bias helps to overcome potential barriers on the reaction path. At the end of many relatively short simulations for each window, the resulting distributions are combined and analyzed, for example, using the Weighted Histogram Analysis Method (WHAM) [102]. Umbrella sampling has often been used to explore the energetic profile of transport of various species through transmembrane channels (e.g. ref [103].), but this method can also be successfully applied to investigate ligand-enzyme binding. For example, umbrella sampling showed good agreement with experimental results for benzonitrile association with wild type and mutant lysozyme T4, and also with MM-PBSA calculations [104].