Extracellular acidification

The disruption of C1C-2 in mice leads to male infertility, blindness, and leukodystrophy, and was attributed to defective extracellular ion homeostasis in narrow clefts. C1C-2 yields currents that slowly activate upon hyperpolarization. It is also activated by cell swelling and by extracellular acidification. Structural determinants that are essential for these types of activation were identified by mutagenesis. There is a report that C1C-2 might be mutated in human epilepsy, but this has not been confirmed in fiuther studies. 

Fig. 20.8. P -gp-ATPase activation profiles obtained by measurements of extracellular acidification rates in living cells by means of a cytosensor physiometer. (A) Cyclosporin A ( ), progesterone (0)> trifluoperazine (A) and verapamil ( ) in LLC-MDR1 cells (B) amitriptyline ( ), calcein-AM (A), diltiazem ( ) and vinblastine (T) in LLC-MDR1 cells.

Cytosensor Microphysiometer technology has been used to detect perturbation in mammalian cells (Hafner, 2000). The system measures small changes in extracellular acidification using a light addressable potentiometric sensor. If the metabolism is interfered with, acid excretion will be affected which could be sensitively measured by LAPS. In principle, this system should be suitable for monitoring pathogen interaction with mammalian cells. 

J. C. Owicki and JW. Parce, Biosensors based on the energy metabolism of living cells the physical chemistry and cell biology of extracellular acidification, Biosens. Bioelectron., 7(4) (1992) 255-272. 

K. Neve, M. Kozlowski and M. Rosser, Dopamine D2 receptor stimulation of Na+/H+ exchange assessed by quantification of extracellular acidification, J. Biol. Chern., 267(36) (1992) 25748-25753. 

P. Gavazzo, S. Paddeu, M. Sartore and C. Nicolini, Study of the relationship between extracellular acidification and cell viability by a silicon-based sensor, Sens. Actuators B Chem., 19(1-3) (1994) 368-372. 

Adebanjo OA, Shankar VS, Pazianas M, Zaidi A, Huang CL-H, Zaidi M. 1994. Modulation of the osteoclast Ca2+ receptor by extracellular protons. Possible linkage between Ca2+ sensing and extracellular acidification. Biochem Biophys Res Communl94 742-747. 

Li YP, Chen W, Liang Y, Li E, Stashenko P. 1999. Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat Genet. 23 447-451. 

Coldwell MC, Boyfield I, Brown AM, Stemp G, Middlemiss DN (1999) Pharmacological characterization of extracellular acidification rate responses in human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells. Br J Pharmacol 727 1135-1144. 

In a range of tissues, D2R activation appears to accelerate Na+/H+ exchange via a pathway that does not involve the inhibition of AC or PTX-sensitive G-proteins (Neve et al., 1992). However in a directly opposite finding, activation of D2R increases extracellular acidification in PTX-manner by inhibiting Na+/H+ exchange (Ganz et al., 1990), indicating the variability that exists between cell lines. 

The toxicity of SM was found to be dependent on extracellular pH. CHO-Kl cell cultures were exposed to SM and the pH was adjusted to between 5 and 10.0. An eightfold increase in LD50 was observed at pH 9.5 compared to pH 5.0. It is possible that SM causes an extracellular acidification through chemical hydrolysis resulting in cytosolic... 

Figure 18.3 P-gp activity profiles measured with living MDR1-transfected cells as a function of drug concentration. The extracellular acidification rate is expressed as a percentage of the basal rate (100%) verapamil is represented by lozenges, lidocaine by open squares, and trifluopromazine by open circles. (Data are taken from Ref. [32].)...

Hynes J, O Riordan TC, Zhdanov AV, Uray G, Will Y et al (2009) In vitro analysis of cell metabolism using a long-decay pH-sensitive lanthanide probe and extracellular acidification assay. Anal Biochem 390 21-28... 

Viglione PN, Pereyra K, Reyes-Toso CF, et al. 1996. Extracellular acidification related to the stimulation of catecholamines release by strontium in the bovine adrenal medulla. Arch Physiol Biochem 104(7) 833-837. 

FIGURE 1A4-1 The cell biology of extracellular acidification. When a receptor is stimulated, signal transduction pathways are Induced. Adenosine triphosphate (ATP) consumption is then compensated by the increased uptake and metabolism of glucose, which results m an increase in the excretion of acid waste products. The extracellular acidification is measured by the LAPS. (From F. Hafner. Biosens. 8/betecfron., 2000. 15. 149. With permission.)... 

Another early application of personalized medicine is the use of microphysiometry, a device that measures the extracellular acidification rate of cells, to establish their sensitivity to chemotherapy [26]. This sensor measures the chemosensitivity by comparing the acidification rate of cells treated with cytostatic agents, such as anticancer drugs, to that of nontreated cells, before a drug is prescribed to the patient. 

Zelenina, M., A. A. Bondar, S. Zelenin and A. Aperia. (2003) Nickel and extracellular acidification inhibit the water permeability of hirmem Aqiraporin-3 in lung epithelial cells. J. Biol. Chem. 

Bozhkov, P.V. Filonova, L.H. von Arnold, S. (2002). A key developmental switch during Norway Spruce somatic embryogenesis is induced by withdrawal of growth regulators and is associated with cell death and extracellular acidification. Biotechnology and Bioengineering, Vol.77, No.6, (January 2002), p>p 658-667, ISSN 1097-0290... 

Exported H -ions from the intracellular space to the interstitial compartment promote extracellular acidification. The latter, together with a HIF-la-induced upreg-ulation of the membrane-bound ectoenzyme carbonic anhydrase (CA IX), finally leads to buffering of the exported protons by extracellular bicarbonate causing a bicarbonate depletion and an intensified CO2 release, both characteric features of the tumor pathophysiome (Fig. 4.22) (Gulling etal. 1965 Gulling 1970, 1975 Vaupel 2008). 

Eklund SE, Cliffel DE, Kozlov E, Prokop A, Wikswo J, Baudenbacher F (2003) Modification of the cytosensor(TM) microphysiometer to simultaneously measure extracellular acidification and oxygen consumption rates. Analytica Chimica Acta 496 93-101... 

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