ENaC regulation by phospholipids and DGK explained through mathematical modeling
Daniel V Olivença1,2, Eberhard O Voit2, Francisco R Pinto3
1Faculty of Sciences, BioISI - Biosystems and Integrative Sciences Institute, University of Lisboa, 1749-016, Lisbon, Portugal.
Scientific Reports
|August 20, 2020
Summary
In cystic fibrosis, altered ion channel function causes thick mucus. Computational modeling reveals diacylglycerol kinase (DGK) inhibition impacts epithelial sodium channels (ENaC) by regulating phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) production.
Area of Science:
- Cellular biology
- Biophysics
- Computational modeling
Background:
- Cystic fibrosis (CF) results from CFTR mutations, affecting ion channel activity.
- Altered epithelial sodium channels (ENaC) contribute to dehydrated mucus and lung inflammation in CF.
- Phosphoinositides regulate cellular processes and membrane proteins like ENaC.
Purpose of the Study:
- To computationally investigate the interaction between diacylglycerol kinase (DGK) and epithelial sodium channels (ENaC).
- To assess the role of DGK in regulating phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and its impact on ENaC activity.
Main Methods:
- Integrated two mathematical models: one for phosphoinositide dynamics, another for PI(4,5)P2's effect on ENaC.
- Performed computational analysis to simulate and assess DGK-ENaC interactions.
Main Results:
- The integrated model accurately reflects literature data on DGK and ENaC.
- Computational results suggest DGK influences ENaC primarily through regulating PI(4,5)P2 synthesis.
- Type-I phosphatidylinositol-4-phosphate 5-kinase (PIP5KI) activity, modulated by phosphatidic acid (PA), is key in this regulation.
Conclusions:
- DGK plays a significant role in regulating ENaC function via PI(4,5)P2 metabolism.
- This study provides a computational framework for understanding ion channel regulation in CF.
- Findings highlight PIP5KI and PA as critical components in the DGK-mediated control of ENaC.
More Related Videos
10:31A Liposome Membrane Permeability Assay for Investigating the Effects of Phosphatidylinositol Phosphate Groups on Membranotropic Action of Venom PLA2
Published on: September 26, 2025
270
08:59Defining Substrate Specificities for Lipase and Phospholipase Candidates
Published on: November 23, 2016
15.4K
Related Concept Videos
01:11IP3/DAG Signaling Pathway
13.8K
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
13.8K
01:22Amplifying Signals via Enzymatic Cascade
16.5K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
16.5K
01:42Phosphoinositides and PIPs
9.9K
Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
9.9K
01:16Calmodulin-dependent Signaling
5.8K
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
5.8K
01:09GPCRs Regulate Adenylyl Cylase Activity
6.7K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
6.7K
01:31Mechanism of Lamellipodia Formation
3.4K
Cells migrating in response to external stimuli form lamellipodia, which are thin membrane protrusions supported by a mesh of linked, branched, or unbranched actin filaments. These actin filaments interact with myosin motor proteins, creating the dynamic actomyosin complex within the cytoskeleton. Contractility, or the ability to generate contractile stress, is inherent to the actomyosin complex. It helps cells detect the stiffness of the surrounding ECM and exert contractile force for...
3.4K