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Review
. 2010 Sep 1;588(Pt 17):3179-85.
doi: 10.1113/jphysiol.2010.192153. Epub 2010 Jun 2.

Phosphoinositides: lipid regulators of membrane proteins

Björn H Falkenburger  1 , Jill B Jensen, Eamonn J Dickson, Byung-Chang Suh, Bertil Hille
Affiliations
Review

Phosphoinositides: lipid regulators of membrane proteins

Björn H Falkenburger et al. J Physiol. .

Abstract

Phosphoinositides are a family of minority acidic phospholipids in cell membranes. Their principal role is instructional: they interact with proteins. Each cellular membrane compartment uses a characteristic species of phosphoinositide. This signature phosphoinositide attracts a specific complement of functionally important, loosely attached peripheral proteins to that membrane. For example, the phosphatidylinositol 4,5-bisphosphate (PIP(2)) of the plasma membrane attracts phospholipase C, protein kinase C, proteins involved in membrane budding and fusion, proteins regulating the actin cytoskeleton, and others. Phosphoinositides also regulate the activity level of the integral membrane proteins. Many ion channels of the plasma membrane need the plasma-membrane-specific PIP(2) to function. Their activity decreases when the abundance of this lipid falls, as for example after activation of phospholipase C. This behaviour is illustrated by the suppression of KCNQ K(+) channel current by activation of M(1) muscarinic receptors; KCNQ channels require PIP(2) for their activity. In summary, phosphoinositides contribute to the selection of peripheral proteins for each membrane and regulate the activity of the integral proteins.

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Figures

Figure 1
Figure 1. Phosphoinositides: diversity, location and recognition
A, generic structure of phosphoinositides, showing three phosphorylatable positions, D3, D4, and D5, on the myo-inositol headgroup. B, the seven polyphosphoinositides and the parent phosphatidyl inositol, their dominant membrane location, and one of several protein domains that recognizes each one. ER: endoplasmic reticulum; MVB: multivesicular bodies.
Figure 2
Figure 2. Phosphoinositide lipid regulation at the plasma membrane and the Golgi
Schematic diagram of some phosphoinositide-dependent processes discussed in the text. The cytoplasmic leaflet of the plasma membrane contains PIP2, and the cytoplasmic leaflet of the Golgi contains PI(4)P. A, open KCNQ channels require PIP2 and are transiently closed when M1 muscarinic receptors activate PLC to cleave and deplete PIP2. B, formation of clathrin-coated pits leading to endocytosis at the plasma membrane involves many PIP2-dependent proteins. C, formation of clathrin-coated pits and budding of vesicles from the Golgi involves a related set of proteins, but now they are PI(4)P-preferring.
Figure 3
Figure 3. Modulation of KCNQ current by M1 receptor activation and by direct dephosphorylation of PIP2
A, metabolic steps that alter PIP2 levels. B, modulation by activation of PLC. Open circles, suppression and recovery of the K+ current when the muscarinic agonist oxotremorine M (Oxo-M, 10 μm) is applied and removed. The whole-cell pipette contains 3 mm ATP to allow PIP2 resynthesis. Filled circles, muscarinic suppression but no recovery when the pipette contains 4 mm of a non-hydrolysable ATP analogue (trinitrophenyl-ATP, TNP-ATP). Without ATP, PIP2 cannot be resynthesized. These experiments use tsA-201 cells as an expression system studied in whole-cell recording. The cells are transfected with the M1 receptor and two channel subunits, KCNQ2 and KCNQ3. (Unpublished data. Methods as in Suh & Hille, 2002.) C, decrease of PIP2 and suppression of current by brief activation of a voltage-sensitive PIP2 5-phosphatase, VSP. The phosphatase is expressed by transfection and activated by a depolarizing voltage pulse at time zero. Filled circles, loss and recovery of PIP2 measured with fluorescence resonance energy transfer (FRET) between CFP and YFP labelled PH domains. Open circles, parallel suppression and recovery of the K+ current. (Unpublished data. Methods as in Falkenburger et al. 2010b.)
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