The role of cytoplasmic-to-lysosomal pH gradient in hydrophobic weak base drug sequestration in lysosomes

2015 ◽  
Keyword(s):  
Ph Gradient ◽  
Weak Base ◽  
Lysosomal Ph ◽  
Drug Sequestration

Effects of quinacrine on calcium active transport by rat intestinal epithelium

1989 ◽  
Vol 257 (5) ◽  
pp. G818-G822 ◽  
Author(s):  
M. J. Favus ◽  
V. Tembe ◽  
M. D. Tanklefsky ◽  
K. A. Ambrosic ◽  
H. N. Nellans
Keyword(s):  
Basolateral Membrane ◽  
Membrane Vesicles ◽  
Weak Base ◽  
Ph Gradients ◽  
Transcellular Transport ◽  
Lysosomal Ph ◽  
Intestinal Segments ◽  
Ca Uptake

To determine the possible role of acidic lysosomal vesicles in the transcellular transport of Ca, bidirectional Ca fluxes were measured across intestinal segments in vitro in the absence of electrochemical gradients. Mucosal addition of the weak base quinacrine (0.2 mM) caused a 67% decline in the mucosal-to-serosal Ca flux (Jm----s) across duodenum (175 +/- 34 vs. 58 +/- 9 nmol.cm-2.h-1, P less than 0.007) and reduced cecal Ca Jm----s (177 +/- 15 vs. 45 +/- 4, P less than 0.0001). Higher concentrations of up to 2.0 mM caused no further decline in cecal Ca Jm----s. Inhibition of cecal Ca Jm----s by mucosal chloroquine (0.1 mM) or ammonium chloride (10 mM) varied from 37 to 50%. Addition in vitro of quinacrine to enterocyte basolateral membrane vesicles failed to inhibit ATP-dependent Ca uptake. The present studies demonstrate that agents that collapse lysosomal pH gradients inhibit transcellular Ca transport. These observations are consistent with the hypothesis that Ca destined for transcellular transport is functionally associated with acidic lysosomes and that these organelles play an important role in transepithelial Ca translocation.

Studies on Lactams

1970 ◽  
Vol 25 (7) ◽  
pp. 665-674 ◽  
Author(s):  
Basanta G. Chatterjee ◽  
Noel L. Nyss
Keyword(s):  
Special Interest ◽  
Weak Base ◽  
Aryl Substituent ◽  
Intramolecular Alkylation ◽  
Electronegative Substituent ◽  
Type 3

The activating influence of a nitrophenyl substituent in the intramolecular alkylation of compounds of the type 3 and 5 has been studied. The investigation establishes that the activation afforded by a 4-nitrophenyl substituent is intermediate between that of a carbonyl and ester functions. The role of the N-aryl substituent in the alkylation of N-aryl, N-α haloacetamino esters and ketones has also been studied. A number of hitherto unreported lactams have been synthesized and characterized. Synthesis of the compound 4 c using a weak base is of special interest, since this lactam possesses only a single electronegative substituent at the 4-position.

A Weak Base-Generating System Suitable for Selective Manipulation of Lysosomal pH

Traffic ◽  
2011 ◽  
Vol 12 (11) ◽  
pp. 1490-1500 ◽  
Author(s):  
Luciene R. Carraro-Lacroix ◽  
Valentin Jaumouillé ◽  
Gregory D. Fairn ◽  
Sergio Grinstein
Keyword(s):  
Weak Base ◽  
Lysosomal Ph ◽  
Generating System

Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin

2005 ◽  
Vol 288 (1) ◽  
pp. C1-C19 ◽  
Author(s):  
Adrian Allen ◽  
Gunnar Flemström
Keyword(s):  
Ph Gradient ◽  
Support Surface ◽  
First Line ◽  
Physiological Conditions ◽  
Neutral Ph ◽  
Primary Function ◽  
Gel Layer ◽  
Mucus Gel ◽  
And Control

Secretion of bicarbonate into the adherent layer of mucus gel creates a pH gradient with a near-neutral pH at the epithelial surfaces in stomach and duodenum, providing the first line of mucosal protection against luminal acid. The continuous adherent mucus layer is also a barrier to luminal pepsin, thereby protecting the underlying mucosa from proteolytic digestion. In this article we review the present state of the gastroduodenal mucus bicarbonate barrier two decades after the first supporting experimental evidence appeared. The primary function of the adherent mucus gel layer is a structural one to create a stable, unstirred layer to support surface neutralization of acid and act as a protective physical barrier against luminal pepsin. Therefore, the emphasis on mucus in this review is on the form and role of the adherent mucus gel layer. The primary function of the mucosal bicarbonate secretion is to neutralize acid diffusing into the mucus gel layer and to be quantitatively sufficient to maintain a near-neutral pH at the mucus-mucosal surface interface. The emphasis on mucosal bicarbonate in this review is on the mechanisms and control of its secretion and the establishment of a surface pH gradient. Evidence suggests that under normal physiological conditions, the mucus bicarbonate barrier is sufficient for protection of the gastric mucosa against acid and pepsin and is even more so for the duodenum.

The Critical Role of pH Gradient Formation in Driving Superconformal Cobalt Deposition

2018 ◽  
Vol 166 (1) ◽  
pp. D3167-D3174 ◽  
Author(s):  
Matthew A. Rigsby ◽  
Lee J. Brogan ◽  
Natalia V. Doubina ◽  
Yihua Liu ◽  
Edward C. Opocensky ◽  
...  
Keyword(s):  
Critical Role ◽  
Ph Gradient ◽  
Gradient Formation ◽  
Cobalt Deposition

scholarly journals Fronto-temporal dementia risk gene TMEM106B has opposing effects in different lysosomal storage disorders

2020 ◽  
Author(s):  
Azucena Perez-Canamas ◽  
Hideyuki Takahashi ◽  
Jane A Lindborg ◽  
Stephen M Strittmatter
Keyword(s):  
Gaucher Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Vacuolar Atpase ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Lysosomal Compartment ◽  
Lysosomal Ph ◽  
Ceroid Lipofuscinosis ◽  
Storage Disorders

Abstract TMEM106B is a transmembrane protein localized to the endo-lysosomal compartment. Genome-wide association studies have identified TMEM106B as a risk modifier of Alzheimer’s disease and frontotemporal lobar degeneration, especially with progranulin haploinsufficiency. We recently demonstrated that TMEM106B loss rescues progranulin null mouse phenotypes including lysosomal enzyme dysregulation, neurodegeneration and behavioural alterations. However, the reason whether TMEM106B is involved in other neurodegenerative lysosomal diseases is unknown. Here, we evaluate the potential role of TMEM106B in modifying the progression of lysosomal storage disorders using progranulin-independent models of Gaucher disease and neuronal ceroid lipofuscinosis. To study Gaucher disease, we employ a pharmacological approach using the inhibitor conduritol B epoxide in wild-type and hypomorphic Tmem106b−/− mice. TMEM106B depletion ameliorates neuronal degeneration and some behavioural abnormalities in the pharmacological model of Gaucher disease, similar to its effect on certain progranulin null phenotypes. In order to examine the role of TMEM106B in neuronal ceroid lipofuscinosis, we crossbred Tmem106b−/− mice with Ppt1−/−, a genetic model of the disease. In contrast to its conduritol B epoxide-rescuing effect, TMEM106B loss exacerbates Purkinje cell degeneration and motor deficits in Ppt1−/− mice. Mechanistically, TMEM106B is known to interact with subunits of the vacuolar ATPase and influence lysosomal acidification. In the pharmacological Gaucher disease model, the acidified lysosomal compartment is enhanced and TMEM106B loss rescues in vivo phenotypes. In contrast, gene-edited neuronal loss of Ppt1 causes a reduction in vacuolar ATPase levels and impairment of the acidified lysosomal compartment, and TMEM106B deletion exacerbates the mouse Ppt1−/− phenotype. Our findings indicate that TMEM106B differentially modulates the progression of the lysosomal storage disorders Gaucher disease and neuronal ceroid lipofuscinosis. The effect of TMEM106B in neurodegeneration varies depending on vacuolar ATPase state and modulation of lysosomal pH. These data suggest TMEM106B as a target for correcting lysosomal pH alterations, and in particular for therapeutic intervention in Gaucher disease and neuronal ceroid lipofuscinosis.

scholarly journals Dual Role for the Tyrosine Decarboxylation Pathway in Enterococcus faecium E17: Response to an Acid Challenge and Generation of a Proton Motive Force

2008 ◽  
Vol 75 (2) ◽  
pp. 345-352 ◽  
Author(s):  
C. I. Pereira ◽  
D. Matos ◽  
M. V. San Romão ◽  
M. T. Barreto Crespo
Keyword(s):  
Membrane Potential ◽  
Enterococcus Faecium ◽  
Proton Motive Force ◽  
Motive Force ◽  
Ph Gradient ◽  
Ph Homeostasis ◽  
Fermentation Products ◽  
Cell Counts ◽  
Acid Challenge

ABSTRACT In this work we investigated the role of the tyrosine decarboxylation pathway in the response of Enterococcus faecium E17 cells to an acid challenge. It was found that 91% of the cells were able to remain viable in the presence of tyrosine when they were incubated for 3 h in a complex medium at pH 2.5. This effect was shown to be related to the tyrosine decarboxylation pathway. Therefore, the role of tyrosine decarboxylation in pH homeostasis was studied. The membrane potential and pH gradient, the parameters that compose the proton motive force (PMF), were measured at different pHs (pH 4.5 to 7). We obtained evidence showing that the tyrosine decarboxylation pathway generates a PMF composed of a pH gradient formed due to proton consumption in the decarboxylation reaction and by a membrane potential which results from electrogenic transport of tyrosine in exchange for the corresponding biogenic amine tyramine. The properties of the tyrosine transporter were also studied in this work by using whole cells and right-side-out vesicles. The results showed that the transporter catalyzes homologous tyrosine/tyrosine antiport, as well as electrogenic heterologous tyrosine-tyramine exchange. The tyrosine transporter had properties of a typical precursor-product exchanger operating in a proton motive decarboxylation pathway. Therefore, the tyrosine decarboxylation pathway contributes to an acid response mechanism in E. faecium E17. This decarboxylation pathway gives the strain a competitive advantage in nutrient-depleted conditions, as well as in harsh acidic environments, and a better chance of survival, which contributes to higher cell counts in food fermentation products.

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