Vacuolar-type proton pump ATPases: roles of subunit isoforms in physiology and pathology

The vacuolar-type H(+)-ATPases (V-ATPases) are a family of multi-subunit ATP-dependent proton pumps involved in diverse cellular processes, including acid/base homeostasis, receptor-mediated endocytosis, processing of proteins and signaling molecules, targeting of lysosomal enzymes, and activation of various degradation enzymes. These fundamental cellular activities are naturally related to higher order physiological functions in multicellular organisms. V-ATPases are involved in several physiological processes, including renal acidification, bone resorption, and neurotransmitter accumulation. Both forward- and reverse-genetic approaches have revealed that V-ATPase malfunction causes diseases and/or pathophysiological states, demonstrating its diverse roles in normal physiology. Here, we focus on the recent insights into the function of mammalian V-ATPase in highly differentiated cells and tissues.