Τόμος 9 (1991) – Τεύχος 3 – Άρθρο 1 – Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Ελληνική Έκδοση – Volume 9 (1991) – Issue 3 – Article 1 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-Greek Edition

9: 133-166 (1991)

PHARMAKON-Press: Epitheorese Klin. Farmakol. Farmakokinet.

9: 133-166 (1991)

Cell membranes, lipid bilayer, cellular proteins, passage of substances, passive diffusion, facilitated diffusion, active transport, carrier-proteins, ionophores, membrane potential, and Na⁺-K⁺ ATPase, receptor-mediated endocytosis, exocytosis

Cell membranes are highly viscous yet plastic structures surrounding all living cells. Their basic structure is the lipid bilayer, a sheetlike structure consisting of two layers of lipid molecules, i.e. phospholipids (phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol), sphingolipids and cholesterol, the lipid molecules are aligned so that their polar heads — glycerly phosphate attached to ethanolamine, choline, serine or inositol in the case of phospholipids, sphin­gosine phosphate attached to chοline in the case of sphingolipids or the terminal hydroxyl group of cholesterol — face the adjacent aqueous milieu, while the hydrophobic portions — hydrocarbon chains of phospholipids and sphingolipids or the main bulk of the chole­sterol molecule — occupy the internal core of the membrane.

Integral (or intrinsic) protein molecules span the full width of the membrane (transmem- brαne proteins); they are embedded in the bilayer by interaction of one or more of their regions with fatty acyl chains in the hydro­phobic core. Peripheral membrane proteins are attached either to integral proteins at the inner side of the membrane by specific protein-protein interactions and are predominantly hydrophilic (like cytoplasmic proteins) or to the hydώphilic ends of lipids at either surface by specific lipid-protein interactions. Transmem­brane proteins are often carrier-proteins which interact selectively with solutes and transfer them into the intracellular space; in some occasions they form channels (channel pro­teins) which facilitate the transport of ions (Na⁺, Κ⁺, Ca²⁺) into the cell. A transmembrane protein is also the Na⁺-Κ⁺ activated ATPase, which consists the physical basis of sodium-potas­sium pump. A number of cellular proteins, localized either on plasma membrane or intra­cellularly, serve as receptors for drugs, neuro­transmitters hormones and other bioactive molecules.

Glycolipids or glycoproteins are formed on the outer surface of the membrane by the attachment of different polymeric arrangement of monosaccharides (galactose, manose, fucose i.e. 6-desoxygalactose), amino-sugar derivatives (N-acetylglucosamine, N-acetyl galactosamine), or one of these condensed with pyruvate: the sialic acids (e.g. N-acetyl neuraminic acid). All these constituents can manifest mobility over periods of minutes to days in a lateral or, in a transverse (flip-flop across the membrane) direction — the fluid mosaic model of biologic membranes. The fluidity, and thus the phase changes of cell membranes, is highly depen­dent upon their lipid composition, while chole­sterol also acts as a moderator molecule producing intermediated states of membrane fluidity.

The inorganic components of cell membra­nes include (a) membrane-bound water which coats polar ionized groups and thus tends to restrict the transverse mobility of proteins; (b) ions (particularly Ca⁺) which can separate negatively charged heads of phospholipids and thus alter the charge distribution within the membrane.

The main functions of cell membranes include (a) transportation of biologic substances or other small molecules into or out of cells; (b) transduction of signals from hormones or drugs acting at receptor sites on the outer side of the membrane to systems in the interior of the cell; (c) anchoring of cytoskeletal elements and components of the extracellular matrix; and (d) enzymic catalysis of metabolic re­actions.

Cell membrane is not only asymmetric morphologically, but also electrically so that excitation or inhibition can occur by an appro­priate alteration of the ionic disposition inside or outside. The plasma membrane, due tο its structure, has selective permeabilities and acts as a barrier, thereby maintaining differences in composition between the inside and the out­side of the cell. The selective permeabilities are provided by channels and pumps for ions and substrates and by specific receptor for signals.

Transport across the plasma membrane can occur (a) by diffusion, either through water-filled pores (ultrafiltration), paracellular spaces or directly via the lipoprotein structure (passive diffusion); the diffusion rate is determined by the differences in substance concentration (outside and inside the cell) and electroche­mical gradient; (b) by protein-carrier-mediated processes which can be either. facilitated diffusion or active transport.

Transport systems can be classified as uniport systems that. move one type of mole­cules bidirectionally and as cotransport sy­stems, in which the transfer of one solute depends upon the stoichiometric transfer (si­multaneous or sequential) of another solute in the same direction (symport systems) or in opposite directions (antiport systems). Facili­tated diffusion proceeds more rapidly than simple diffusion due to the intervention of a specific, saturable carrier system, but cannot occur against a gradient. Active movements can proceed against concentration, electrical, hydrostatic or osmotic gradients producing a selective concentration of a particular sub­stance at one side of a biological membrane; these movements require an energy supply and, often in addition, a carrier substance, e.g. Na⁺, K⁺, Mg-activated ATPase. Carrier-mole­cules are often transmembrane proteins which exist in 2 main conformational states. In the one state the carrier molecule is exposed to high concentrations of solute and/or has one or more specific binding sites of high affinity for the solute. Transport occurs when a conformational change exposes the carrier molecule to a lower concentration of solute and/or in this second conformational state the affinity of the solute for the binding sites is lesser than in the other state. Conformations change may be due either to the formation of the carrier-solute complex (facilitated diffusion) or to the ATP hydrolysis or to an ion gradient.

Some antibiotics act by facilitating the passage of specific ions across membrane (ionophores); these molecules contain hydro­philic centers that bind the ions and are surrounded by peripheral hydrophobic regions, thereby forming a three-dimensional        cage which allows the molecules to dissolve in the membrane and diffuse therein.

Macromolecules, such as some peptide hormones, growth factors, antιbοdies and other substances, can traverse the cell membrane by fluid-phase pinocytosis, and by receptor-media­ted endocytosis. The latter process is selective and occurs in coated pits lined with the protein clathrin, a peripheral membrane protein. These coated pits become pinched off from the cell surface to form coated vesicles. After inter­nalization, the vesicles shed their clathrin coats and then fuse with one another to form endosomes. The receptor-ligand complexes fol­low one of these four pathways: (a) the receptor is recycled and the ligant degra­ded; (b) both the receptor and the ligand are recycled; (c) both the receptor and the ligand are degraded; and (d) both the receptor and the ligand are transported to another cell surface. Most cells also release macromolecules to the exterior by exocytosis.

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