Novel Insights Into V-ATPase Functioning: Distinct Roles for Its Accessory Subunits ATP6AP1/Ac45 and ATP6AP2/(pro) Renin Receptor

Curr Protein Pept Sci. 2012 Mar;13(2):124-33. doi: 10.2174/138920312800493160.

Abstract

The vacuolar (H+)-ATPase (V-ATPase) is a universal proton pump and its activity is required for a variety of cell-biological processes such as membrane trafficking, receptor-mediated endocytosis, lysosomal protein degradation, osteoclastic bone resorption and maintenance of acid-base homeostasis by renal intercalated cells. In neuronal and neuroendocrine cells, the V-ATPase is the major regulator of intragranular acidification which is indispensable for correct prohormone processing and neurotransmitter uptake. In these specialized cells, the V-ATPase is equipped with the accessory subunits ATP6AP1/Ac45 and ATP6AP2/(pro) renin receptor. Recent studies have shown that Ac45 interacts with the V0- sector of the V-ATPase complex, thereby regulating the intragranular pH and Ca2+-dependent exocytotic membrane fusion. Thus, Ac45 can be considered as a V-ATPase regulator in the neuroendocrine secretory pathway. ATP6AP2 has recently been found to be identical to the (pro) renin receptor and has a dual role: (i) in the renin-angiotensin system that also regulates V-ATPase activity; (ii) acting as an adapter by binding to both the V-ATPase and the Wnt receptor complex, thereby recruiting the receptor complex into an acidic microenvironment. We here provide an overview of the two V-ATPase accessory subunits as novel key players in V-ATPase regulation. We argue that the accessory subunits are candidate genes for V-ATPase-related human disorders and promising targets for manipulating V-ATPase functioning in vivo.

Publication types

  • Review

MeSH terms

  • Animals
  • Gene Expression Regulation, Developmental
  • Humans
  • Membrane Fusion
  • Protein Subunits / chemistry
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Receptors, Cell Surface / metabolism*
  • Renin / metabolism*
  • Renin-Angiotensin System
  • Secretory Pathway
  • Vacuolar Proton-Translocating ATPases / chemistry
  • Vacuolar Proton-Translocating ATPases / genetics
  • Vacuolar Proton-Translocating ATPases / metabolism*

Substances

  • Protein Subunits
  • Receptors, Cell Surface
  • Renin
  • Vacuolar Proton-Translocating ATPases