V-ATPase functions in normal and disease processes

Abstract

Eukaryotic cells have evolved a family of ATP-dependent proton pumps known as the vacuolar (H(+))-ATPases (or V-ATPases) to regulate the pH of intracellular compartments, the extracellular space, and the cytoplasm. V-ATPases present within intracellular compartments are important for such normal cellular processes as receptor-mediated endocytosis and intracellular membrane traffic, protein processing and degradation and coupled transport of small molecules and ions. They also facilitate the entry of a number of envelope viruses and bacterial toxins, including influenza virus and anthrax toxin. V-ATPases present in the plasma membranes of cells are also important in normal physiology. They facilitate bone resorption by osteoclasts, acid secretion by intercalated cells of the kidney, pH homeostasis in macrophages and neutrophils, angiogenesis by endothelial cells, and sperm maturation and storage in the male reproductive tract. In the insect midgut, they establish a membrane potential used to drive K(+) secretion. Plasma membrane V-ATPases are especially important in human disease, with genetic defects in V-ATPases expressed in osteoclasts and intercalated cells leading to the diseases osteopetrosis and renal tubule acidosis, respectively. Plasma membrane V-ATPases have also been implicated in tumor cell invasion. V-ATPases are thus emerging as potential targets in the treatment of diseases such as osteoporosis and cancer.

Enoxacin Directly Inhibits Osteoclastogenesis without Inducing Apoptosis

“…V-ATPases are essential "housekeeping" enzymes in all eukaryotic cells that are necessary for the acidification of compartments of the endocytic and phagocytic pathways (6,7). Most cell types express only the low levels of V-ATPase required to carry out housekeeping functions, but some cell types also contain an additional subset of V-ATPases that plays * This work was supported, in whole or in part, by National Institutes of Health a role in the unique functions of the cell.…”

Antiviral drug discovery: broad-spectrum drugs from nature

“…This activity is important for the function and trafficking of internal organelles such as vacuoles, endosomes, or lysosomes, which are in turn used by viruses for entry, translation, assembly or budding 261,262 . However, blocking these proton pumps also leads to other physiological changes in the host cell ( 263 and references therein), and thus the benefit-risk ratio of such compounds as BSAs in vivo remains to be determined.…”

A research‐based laboratory course designed to strengthen the research‐teaching nexus

“…Mechanical rotation of a central shaft that extends from V 1 to V o and consists of various subunits, including the subunit d, couples ATP hydrolysis, and proton transport. The structural complexity of these membrane transporters, their fascinating mechanism of rotational catalysis, and their link to several types of cancers and kidney, muscle, and bone diseases [8][9][10][11] helped capture the research laboratory course students' attention and curiosity. The yeast S. cerevisiae was employed as the model organism in this research laboratory course not only because it is the system used by the primary author in her own work, but because it is an inexpensive, safe, and powerful research tool suitable for undergraduate research and teaching [12][13][14][15][16].…”

“…Mechanical rotation of a central shaft that extends from V 1 to V o and consists of various subunits, including the subunit d, couples ATP hydrolysis, and proton transport. The structural complexity of these membrane transporters, their fascinating mechanism of rotational catalysis, and their link to several types of cancers and kidney, muscle, and bone diseases [8][9][10][11] helped capture the research laboratory course students' attention and curiosity.…”