Effect of the lipid environment on receptor clustering and function

The cell membrane cannot be considered a homogenous system from the standpoint of lipids or proteins since both types of molecules constitute assemblies of varying temporal and spatial stability. The hierarchical association of membrane proteins represent such a structure, but lipid microdomains also belong to them. Lipid rafts are such supramolecular organization of lipids, which are thermodynamically unstable, small (10-100 nm) structures. Proteins, lipids, the cytoskeleton and membrane turnover all contribute to their generation. They are similar, but not identical, in many respects to the liquid-ordered (Lo) domains in model membranes. The lipid environment of the cell membrane obviously influences the biophysical and cell biological properties of transmembrane proteins through their transmembrane domain. An important property of the cell membrane is the dipole potential, which is a positive potential of magnitude 200-500 mV in the interior of the cell membrane generated by the dipoles of lipids and membrane-associated water molecules. This electric field interacts with transmembrane protein (due to the dipole moment of their transmembrane domain), with ligands and molecules binding to cell surface receptors or being transported across the membrane.

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Penetratin is a cell-penetrating peptide having a potential role in efficient and targeted delivery of drugs. It enters the cytoplasm of cells either by direct membrane crossing or by endocytosis followed by traversing the membrane of the endo-lysosomal compartment (figure on the top). Due to the charged nature of penetratin, the positive intramembrane dipole potential inhibits in membrane crossing. Decreasing the dipole potential with atorvastatin treatment resulted in a significantly enhanced concentration of penetratin in the cytosol (figure at the bottom).