Dataset Information

Phosphoinositides in the kidney.

ABSTRACT: Phosphoinositides (PIs) play pivotal roles in the regulation of many biological processes. The quality and quantity of PIs is regulated in time and space by the activity of PI kinases and PI phosphatases. The number of PI-metabolizing enzymes exceeds the number of PIs with, in many cases, more than one enzyme controlling the same biochemical step. This would suggest that the PI system has an intrinsic ability to buffer and compensate for the absence of a specific enzymatic activity. However, there are several examples of severe inherited human diseases caused by mutations in one of the PI enzymes, although other enzymes with the same activity are fully functional. The kidney depends strictly on PIs for physiological processes, such as cell polarization, filtration, solute reabsorption, and signal transduction. Indeed, alteration of the PI system in the kidney very often results in pathological conditions, both inherited and acquired. Most of the knowledge of the roles that PIs play in the kidney comes from the study of KO animal models for genes encoding PI enzymes and from the study of human genetic diseases, such as Lowe syndrome/Dent disease 2 and Joubert syndrome, caused by mutations in the genes encoding the PI phosphatases, OCRL and INPP5E, respectively.

SUBMITTER: Staiano L

PROVIDER: S-EPMC6358291 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Phosphoinositides in the kidney.

Staiano Leopoldo L De Matteis Maria Antonietta MA

Journal of lipid research 20181012 2

Phosphoinositides (PIs) play pivotal roles in the regulation of many biological processes. The quality and quantity of PIs is regulated in time and space by the activity of PI kinases and PI phosphatases. The number of PI-metabolizing enzymes exceeds the number of PIs with, in many cases, more than one enzyme controlling the same biochemical step. This would suggest that the PI system has an intrinsic ability to buffer and compensate for the absence of a specific enzymatic activity. However, the ...[more]

PMID: 30314999

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Project description:Phosphatidylinositol-4,5-bisphosphate (PIP2), which constitutes ?1% of the plasma membrane phospholipid, plays a key role in membrane-delimited signaling. PIP2 regulates structurally and functionally diverse membrane proteins, including voltage- and ligand-gated ion channels, inwardly rectifying ion channels, transporters, and receptors. In some cases, the regulation is known to involve specific lipid-protein interactions, but the mechanisms by which PIP2 regulates many of its various targets remain to be fully elucidated. Because many PIP2 targets are membrane-spanning proteins, we explored whether the phosphoinositides might alter bilayer physical properties such as curvature and elasticity, which would alter the equilibrium between membrane protein conformational states-and thereby protein function. Taking advantage of the gramicidin A (gA) channels' sensitivity to changes in lipid bilayer properties, we used gA-based fluorescence quenching and single-channel assays to examine the effects of long-chain PIP2s (brain PIP2, which is predominantly 1-stearyl-2-arachidonyl-PIP2, and dioleoyl-PIP2) on bilayer properties. When premixed with dioleoyl-phosphocholine at 2 mol %, both long-chain PIP2s produced similar changes in gA channel function (bilayer properties); when applied through the aqueous solution, however, brain PIP2 was a more potent modifier than dioleoyl-PIP2. Given the widespread use of short-chain dioctanoyl-phosphoinositides, we also examined the effects of diC8-phosphoinositol (PI), PI(4,5)P2, PI(3,5)P2, PI(3,4)P2, and PI(3,4,5)P3. The diC8 phosphoinositides, except for PI(3,5)P2, altered bilayer properties with potencies that decreased with increasing head group charge. Nonphosphoinositide diC8 phospholipids generally were more potent bilayer modifiers than the polyphosphoinositides. These results show that physiological increases or decreases in plasma membrane PIP2 levels, as a result of activation of PI kinases or phosphatases, are likely to alter lipid bilayer properties, in addition to any other effects they may have. The results further show that exogenous PIP2, as well as structural analogues that differ in acyl chain length or phosphorylation state, alters lipid bilayer properties at the concentrations used in many cell physiological experiments.

Dataset Information

Phosphoinositides in the kidney.

Publications

Phosphoinositides in the kidney.

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