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

[ Vol. 13 , Issue. 2 ]

Author(s):

Eric J.R. Jansen and Gerard J.M. Martens   Pages 124 - 133 ( 10 )

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.

Keywords:

Acidification, secretory pathway, membrane fusion, neurodevelopment, osteoporosis, renin-angiotensin system, endocytosis, teoclasts, eurotransmitter transporters, F-ATPase complex

Affiliation:

Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, and Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University, Geert Grooteplein Zuid 28, 6525 GA Nijmegen, The Netherlands.



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