Plasma membrane K+/H+‐ATPase From leishmania donovani

Jiang, Suping; Anderson, Steven A.; Winget, G.Douglas; Mukkada, Antony J.

doi:10.1002/jcp.1041590109

Cited by 31 publications

(26 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, the parasite must possess robust acid extrusion machinery to resist a drop in intracellular pH resulting from rapid influx of protons and also from generation of metabolic acids. A dicyclohexylcarbodiimide-sensitive plasma membrane H + -ATPase has been implicated in regulating the intracellular pH of Leishmania (Marchesini and Docampo, 2002 (Jiang et al, 1994). However, direct involvement of this protontranslocating ATPase in counteracting acid stress in Leishmania remains to be established.…”

Section: Discussionmentioning

confidence: 99%

“…Proton extrusion from the cytosol, mediated by a membrane-bound H + -ATPase, has been implicated in regulating the intracellular pH of the parasite (Marchesini and Docampo, 2002;Jiang et al, 1994). However, the role of this ATPase is yet to be established in Leishmania cells growing within host macrophages or under in vitro conditions when the extracellular pH is close to the lysosomal pH (∼5.0).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Interplay between a cytosolic and a cell surface carbonic anhydrase in pH homeostasis and acid tolerance of Leishmania

Pal

Abbasi

Mondal

et al. 2017

Journal of Cell Science

View full text Add to dashboard Cite

Leishmania parasites have evolved to endure the acidic phagolysosomal environment within host macrophages. How Leishmania cells maintain near-neutral intracellular pH and proliferate in such a proton-rich mileu remains poorly understood. We report here that, in order to thrive in acidic conditions, Leishmania major relies on a cytosolic and a cell surface carbonic anhydrase, LmCA1 and LmCA2, respectively. Upon exposure to acidic medium, the intracellular pH of the LmCA1 +/− , LmCA2 +/− and LmCA1 +/− :LmCA2 +/− mutant strains dropped by varying extents that led to cell cycle delay, growth retardation and morphological abnormalities. Intracellular acidosis and growth defects of the mutant strains could be reverted by genetic complementation or supplementation with bicarbonate. When J774A.1 macrophages were infected with the mutant strains, they exhibited much lower intracellular parasite burdens than their wild-type counterparts. However, these differences in intracellular parasite burden between the wild-type and mutant strains were abrogated if, before infection, the macrophages were treated with chloroquine to alkalize their phagolysosomes. Taken together, our results demonstrate that haploinsufficiency of LmCA1 and/or LmCA2 renders the parasite acid-susceptible, thereby unravelling a carbonic anhydrase-mediated pH homeostatic circuit in Leishmania cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interplay between a cytosolic and a cell surface carbonic anhydrase in pH homeostasis and acid tolerance of Leishmania

Pal

Abbasi

Mondal

et al. 2017

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…The apparent K m for Na ϩ in this system was estimated to be ϳ6 mM; however, this analysis was complicated by the presence of both a saturable and a linear transport component (24) and, in any case, the role of a Na ϩ /H ϩ exchanger in pH i regulation in this organism has recently been questioned (12). Leishmania promastigotes have also been proposed to possess an Na exchanger involved in pH control (35); however, this too has been disputed (36).…”

Section: Fig 4 Effect Of Extracellular Namentioning

confidence: 99%

Na+-dependent pH Regulation by the Amitochondriate Protozoan Parasite Giardia intestinalis

Biagini¹,

Knodler²,

Saliba³

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

Giardia intestinalis is a pathogenic fermentative parasite, which inhabits the gastrointestinal tract of animals and humans. G. intestinalis trophozoites are exposed to acidic fluctuations in vivo and must also cope with acidic metabolic endproducts. In this study, a combination of independent techniques ( 31 P NMR spectroscopy, distribution of the weak acid pH marker 5,5-dimethyl-2,4-oxazolidinedione (DMO) and the fluorescent pH indicator 2,7-bis (carboxyethyl)-5,6-carboxyfluorescein (BCECF)) were used to show that G. intestinalis trophozoites exposed to an extracellular pH range of 6.0-7.5 maintain their cytosolic pH (pH i ) within the range 6.7-7.1. Maintenance of the resting pH i was Na ؉ -dependent but unaffected by amiloride (or analogs thereof). Recovery of pH i from an intracellular acidosis was also Na ؉ -dependent, with the rate of recovery varying with the extracellular Na ؉ concentration in a saturable manner (K m ‫؍‬ 18 mM; V max ‫؍‬ 10 mM H ؉ min ؊1

show abstract

“…Nutrient uptake occurs through a proton symport mechanism (10,19), but it comes at a cost to the parasite in the accumulation of protons inside. This is countered by a P-type K ϩ ,H ϩ -ATPase situated on the surface membrane of the parasite, which pumps the protons out (2,3,12,19). This enables the amastigote to maintain a stable and neutral internal pH within the proton-rich phagolysosomes.…”

mentioning

confidence: 99%

Antileishmanial Activity of the Antiulcer Agent Omeprazole

Jiang

Meadows

Anderson

et al. 2002

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

The benzimidazole compound omeprazole, used widely for the treatment of peptic ulcer disease, inhibits the growth of Leishmania donovani, the causative agent of visceral leishmaniasis. Promastigotes cultured at acidic pH and amastigotes within infected macrophages are reduced 90% or more with 150 M omeprazole. Antiparasitic action of the drug is due to its inhibition of the P-type K ؉ ,H ؉ -ATPase on the surface membrane. This enzyme is important for pH homeostasis and the maintenance of proton motive force across the membrane in Leishmania. The drug is effective only at acidic pH, a condition that mimics the in vivo environment within the phagolysosomal vesicles where the amastigote form of the parasite resides. Omeprazole deserves consideration as an alternative to currently available chemotherapeutics, which have severe toxic side effects.

show abstract

Plasma membrane K⁺/H⁺‐ATPase From leishmania donovani

Cited by 31 publications

References 24 publications

Interplay between a cytosolic and a cell surface carbonic anhydrase in pH homeostasis and acid tolerance of Leishmania

Interplay between a cytosolic and a cell surface carbonic anhydrase in pH homeostasis and acid tolerance of Leishmania

Na+-dependent pH Regulation by the Amitochondriate Protozoan Parasite Giardia intestinalis

Antileishmanial Activity of the Antiulcer Agent Omeprazole

Contact Info

Product

Resources

About