Internalisation

Cathepsins are intracellular proteinases that reside within lysosomes or specific intracellular granules. Cathepsins are used to degrade proteins or pqffides that are internalised from the extracellular space. Some cathepsins such as cathepsin-G or cathepsin-K may be released from the cell to degrade specific extracellular matrix proteins. All cathepsins except cathepsin-G (serine) and cathepsin-D (aspartyl) are cysteine proteinases. 

NHE5. The distribution of this isoform is distinct, being in neuronal-rich areas of the central nervous system. Low levels have also been found in testis, spleen and skeletal muscle. Like the preceding isoforms, NHE5 is found in the plasma membrane and is internalised by clathrin-associated endocytosis into recycling endosomes. The normal role of NHE5 is unknown but its malfunction is speculated to contribute to the development of neurodegenerative disease. 

Phagocytes are a group of cells that may engulf and internalise antigens, pathogens or apoptotic cells and destroy them. 

The corpnscnlar theory does provide explanations for phenomena but how far are these internalised by stndents Many continue to reason in macroscopic terms about events, even after being tanght corpuscular theory. 

FIGURE 10 Several pathways of drug internalisation after immuno-specific binding of the immunoUposome to the appropriate cell. (From Peeters et al., 1987.)... 

Heterologous desensitisation refers to the desensitisation of the response to one agonist by the application of a different agonist. For example, desensitisation of a response to adrenaline by application of 5-HT is mediated by protein kinase A or protein kinase C because these kinases can phosphorylate receptors which are not occupied by agonist. Phosphorylation disrupts the receptor-G-protein interaction and induces the binding of specific proteins, arrestins which enhance receptors internalisation via clathrin-coated pits. Thus desensitisation of G-protein-coupled receptors results in a decrease in the number of functional receptors on the cell surface. 

Fig. 2.1 Sequence of events in atherogenesis and role of low-density lipoprotein. Native LDL, in the subendothelial space, undergoes progressive oxidation (mmLDL) and activates the expression of MCP-1 and M-CSF in the endothelium (EC). MCP-1 and M-CSF promote the entry and maturation of monocytes to macrophages, which further oxidise LDL (oxLDL). Ox-LDL is specifically recognised by the scavenger receptor of macrophages and, once internalised, formation of foam cells occurs. Both mmLDL and oxLDL induce endothelial dysfunction, associated with changes of the adhesiveness to leukoc)des or platelets and to wall permeability.

Lorenzi, I, von Eckardstein, A, Cavelier, C, Radosavljevic, S, and Rohrer, L, 2008. Apolipoprotein A-I but not high-density lipoproteins are internalised by RAW macrophages Roles of ATP-binding cassette transporter A1 and scavenger receptor BI. JMolMed 86, 171-183. 

The actual processes of uptake of chemical species by an organism typically encompass transport in the medium, adsorption at extracellular cell wall components, and internalisation by transfer through the cell membrane. Each of these steps constitutes a broad spectrum of physicochemical aspects, including chemical interactions between relevant components, electrostatic interactions, elementary chemical kinetics (in this volume, as pertains to the interface), diffusion limitations of mass transfer processes, etc. 

Dynamics of Biouptake Processes the Role of Transport, Adsorption and Internalisation... 

Adsorption Sites Coupled to First-Order Internalisation Processes. 150... 

Modelling biouptake processes helps in the understanding of the key factors involved and their interconnection [1]. In this chapter, uptake is considered in a general sense, without distinction between nutrition or toxicity, in which several elementary processes come together, and among which we highlight diffusion, adsorption and internalisation [2-4], We show how the combination of the equations corresponding with a few elementary physical laws leads to a complex behaviour which can be physically relevant. Some reviews on the subject, from different perspectives, are available in the literature [2,5-7]. 

Let us consider the uptake of a given species, either a nutrient or a pollutant heavy metal or an organic (macro)molecule, etc., which will be referred to as M. M is present in the bulk of the medium at a concentration, c, ar d we assume that the only relevant mode of transport from the medium to the organism s surface is diffusion. The internalisation sites are taken to be located on the spherical surface of the microorganism or in a semi-spherical surface of a specialised region of the organism with radius ro (see Figure 1). Thus, diffusion prescribes ... 

Figure 1. Outline of the uptake model showing the spherical diffusion of species M through the medium towards two different sites where adsorption is followed by internalisation. The radius of the organism is taken as ro...

Once adsorbed, we assume that M is internalised following a first-order kinetic process in each of the sites, with internalisation rate constants k and k2 respectively [9,16-18], For each kind of adsorption site, we have an uptake flux given by ... 

Figure 2 plots the evolution of the incoming fluxes Jm and with time for some typical values from the literature [24,25] and references therein. As expected, the diffusive flux Jm decreases with time and tends towards a steady-state value when converging with Ju. It is noticeable that, in the initial transient, the internalisation flux Ju is much closer to its eventual steady-state... 

Figure 2. Evolution of diffusive (Jm, continuous line) and internalisation (/u, circles) fluxes with time for a system with two internalisation sites (Section 2.1.2). Fraction of coverages of each site type, 81 and 82, are indicated with dashed lines. Parameters Dm = 10-9m2 s 1,= l(E4molm 3,r0 = l(E4m,Km,i = l(E5molm 3, Am,2 = 10 3 molm 3,rmax,i = 10 8molm 2,rmax,2 = 10 n molm 2, i = 10 2s 1 and kj = 1 s 1...

A Particular Case One Internalisation Route and One Adsorption-Only Route... 

We deal now with two parallel Langmuir adsorption steps, only one of which is followed by internalisation. Parameters of the site with both adsorption and internalisation will be denoted with subscript 1 (physiologically active site), while the other, with no internalisation, will be denoted with subscript 2 (physiologically inactive site) [2]. 

THE STEADY-STATE LIMIT FOR TWO PARALLEL INTERNALISATION ROUTES... 

This expression has been interpreted as the total resistance , being the sum of the diffusion (ro/Asi) and adsorption + internalisation (l/kKn) resistances [11,32] or a combination of permeabilities [19]. If the couple adsorption + internalisation is much more effective than diffusion (kKh > T>m/to), then r// 0 and we recover the steady-state maximum uptake flux for a spherical... 

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