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Am J Physiol Cell Physiol
2017 Jul 01;3131:C42-C53. doi: 10.1152/ajpcell.00244.2016.
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ENaC activity is regulated by calpain-2 proteolysis of MARCKS proteins.
Montgomery DS
,
Yu L
,
Ghazi ZM
,
Thai TL
,
Al-Khalili O
,
Ma HP
,
Eaton DC
,
Alli AA
.
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We previously demonstrated a role for the myristoylated alanine-rich C kinase substrate (MARCKS) to serve as an adaptor protein in the anionic phospholipid phosphate-dependent regulation of the epithelial sodium channel (ENaC). Both MARCKS and ENaC are regulated by proteolysis. Calpains are a family of ubiquitously expressed intracellular Ca2+-dependent cysteine proteases involved in signal transduction. Here we examine the role of calpain-2 in regulating MARCKS and ENaC in cultured renal epithelial cells and in the mouse kidney. Using recombinant fusion proteins, we show that MARCKS, but not the ENaC subunits, are a substrate of calpain-2 in the presence of Ca2+ Pharmacological inhibition of calpain-2 alters MARCKS protein expression in light-density sucrose gradient fractions from cell lysates of mouse cortical collecting duct cells. Calpain-dependent cleaved products of MARCKS are detectable in cultured renal cells. Ca2+ mobilization and calpain-2 inhibition decrease the association between ENaC and MARCKS. The inhibition of calpain-2 reduces ENaC activity as demonstrated by single-channel patch-clamp recordings and transepithelial current measurements. These results suggest that calpain-2 proteolysis of MARCKS promotes its interaction with lipids and ENaC at the plasma membrane to allow for the phosphatidylinositol 4,5-bisphosphate (PIP2)-dependent regulation of ENaC activity in the kidney.
Aderem,
The MARCKS brothers: a family of protein kinase C substrates.
1992, Pubmed
Aderem,
The MARCKS brothers: a family of protein kinase C substrates.
1992,
Pubmed
Aki,
Phosphoinositide 3-kinase accelerates calpain-dependent proteolysis of fodrin during hypoxic cell death.
2002,
Pubmed
Alli,
Molecular approaches to examine the phosphorylation state of the C type natriuretic peptide receptor.
2010,
Pubmed
Alli,
Phosphatidylinositol phosphate-dependent regulation of Xenopus ENaC by MARCKS protein.
2012,
Pubmed
,
Xenbase
Alli,
Calmodulin and CaMKII modulate ENaC activity by regulating the association of MARCKS and the cytoskeleton with the apical membrane.
2015,
Pubmed
,
Xenbase
Alli,
Cathepsin B is secreted apically from Xenopus 2F3 cells and cleaves the epithelial sodium channel (ENaC) to increase its activity.
2012,
Pubmed
,
Xenbase
Arthur,
Investigation of the interaction of m-calpain with phospholipids: calpain-phospholipid interactions.
1996,
Pubmed
Blackshear,
The MARCKS family of cellular protein kinase C substrates.
1993,
Pubmed
Bruns,
Epithelial Na+ channels are fully activated by furin- and prostasin-dependent release of an inhibitory peptide from the gamma-subunit.
2007,
Pubmed
,
Xenbase
Caldwell,
Neutrophil elastase activates near-silent epithelial Na+ channels and increases airway epithelial Na+ transport.
2005,
Pubmed
Campbell,
Structure-function relationships in calpains.
2012,
Pubmed
Canessa,
Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.
1994,
Pubmed
,
Xenbase
Cantiello,
Role of the actin cytoskeleton on epithelial Na+ channel regulation.
1995,
Pubmed
Chakraborti,
Implications of calpains in health and diseases.
2012,
Pubmed
Cressman,
Proteolysis of protein kinase C: mM and microM calcium-requiring calpains have different abilities to generate, and degrade the free catalytic subunit, protein kinase M.
1995,
Pubmed
Domańska-Janik,
Phosphorylation of protein kinase C substrate proteins in rat hippocampal slices--effect of calpain inhibition.
1998,
Pubmed
Dulong,
Myristoylated alanine-rich C kinase substrate (MARCKS) is involved in myoblast fusion through its regulation by protein kinase Calpha and calpain proteolytic cleavage.
2004,
Pubmed
Dwyer-Nield,
Cytoskeletal architecture in mouse lung epithelial cells is regulated by protein-kinase C-alpha and calpain II.
1996,
Pubmed
Floyd,
Differential mechanisms of bicalutamide-induced apoptosis in prostate cell lines.
2009,
Pubmed
Friedrich,
The intriguing Ca2+ requirement of calpain activation.
2004,
Pubmed
Gorlin,
Human endothelial actin-binding protein (ABP-280, nonmuscle filamin): a molecular leaf spring.
1990,
Pubmed
Goudenege,
Biologically active milli-calpain associated with caveolae is involved in a spatially compartmentalised signalling involving protein kinase C alpha and myristoylated alanine-rich C-kinase substrate (MARCKS).
2005,
Pubmed
Haerteis,
Proteolytic activation of the epithelial sodium channel (ENaC) by the cysteine protease cathepsin-S.
2012,
Pubmed
,
Xenbase
Hilgemann,
The complex and intriguing lives of PIP2 with ion channels and transporters.
2001,
Pubmed
Hughey,
Epithelial sodium channels are activated by furin-dependent proteolysis.
2004,
Pubmed
,
Xenbase
Karpushev,
Intact cytoskeleton is required for small G protein dependent activation of the epithelial Na+ channel.
2010,
Pubmed
Kishimoto,
Limited proteolysis of protein kinase C subspecies by calcium-dependent neutral protease (calpain).
1989,
Pubmed
Kleyman,
ENaC at the cutting edge: regulation of epithelial sodium channels by proteases.
2009,
Pubmed
Lampe,
Calpain and MARCKS protein regulation of airway mucin secretion.
2012,
Pubmed
Ma,
Acute regulation of epithelial sodium channel by anionic phospholipids.
2005,
Pubmed
McLaughlin,
Plasma membrane phosphoinositide organization by protein electrostatics.
2005,
Pubmed
Mellgren,
Calcium-dependent proteases: an enzyme system active at cellular membranes?
1987,
Pubmed
Mikawa,
Studies on proteolysis of protein kinase C with calpain I and II.
1990,
Pubmed
Passero,
Plasmin activates epithelial Na+ channels by cleaving the gamma subunit.
2008,
Pubmed
,
Xenbase
Patel,
Tissue kallikrein activation of the epithelial Na channel.
2012,
Pubmed
,
Xenbase
Pochynyuk,
Regulation of the epithelial Na+ channel (ENaC) by phosphatidylinositides.
2006,
Pubmed
Pánico,
Role of calpain-10 in the development of diabetes mellitus and its complications.
2014,
Pubmed
Reifenberger,
Cytochalasin E alters the cytoskeleton and decreases ENaC activity in Xenopus 2F3 cells.
2014,
Pubmed
,
Xenbase
Saido,
Proteolysis of protein kinase C by calpain: effect of acidic phospholipids.
1991,
Pubmed
Seykora,
Molecular determinants of the myristoyl-electrostatic switch of MARCKS.
1996,
Pubmed
Suzuki,
Structure, activation, and biology of calpain.
2004,
Pubmed
Wang,
Calpain activation by ROS mediates human ether-a-go-go-related gene protein degradation by intermittent hypoxia.
2016,
Pubmed
Wendt,
Interaction of calpastatin with calpain: a review.
2004,
Pubmed
Yue,
Phosphatidylinositol 4,5-bisphosphate (PIP2) stimulates epithelial sodium channel activity in A6 cells.
2002,
Pubmed
,
Xenbase
