The Cell Membrane. To the phosporic acid group an other polar atomic group is connected. phosphatidylethanolamin. phosphatidylserin,

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1 The Cell Membrane The cell membrane functions as a semi-permeable barrier, allowing a very few molecules across it while fencing the majority of organically produced chemicals inside the cell. Electron microscopic examinations of cell membranes have led to the development of the lipid bilayer model (also referred to as the fluid-mosaic model). The most common molecule in the model is the phospholipid, which has a polar (hydrophilic) head and two nonpolar (hydrophobic) tails. These phospholipids are aligned tail to tail so the nonpolar areas form a hydrophobic region between the hydrophilic heads on the inner and outer surfaces of the membrane. This layering is termed a bilayer since an electron microscopic technique known as freeze-fracturing is able to split the bilayer. Phospholipids and glycolipids are important structural components of cell membranes. Phospholipids are modified so that a phosphate group (PO 4 - ) replaces one of the three fatty acids normally found on a lipid. The addition of this group makes a polar "head" and two nonpolar "tails". To the phosporic acid group an other polar atomic group is connected e.g.: phosphatidylethanolamin phosphatidylserin, phosphatidylcholine phosphatidylinositol

2 Phospholipids are 2 fatty acids one saturated and one unsaturated (shown by the double bond) that are linked to a glycerol.

3 Cholesterol is another important component of cell membranes embedded in the hydrophobic areas of the inner (tail-tail) region. Most bacterial cell membranes and the plant cell membranes do not contain cholesterol. A koleszterin molekuláknak számos funkciója van a membránban: * Immobilizálják a foszolipid molekulák első néhány szénhidrogén csoportját. Ez a lipid kettősréteget a deformációval szemben ellenállóbbá teszi és lecsökkenti a kis vízoldható molekulák permeabilitását a membránon át. Koleszterin nélkül a sejteknek sejtfalra lenne szüksége. * A koleszterin gátolja a szénhidrogének kristályosodását és a fázis átalakulási hőmérséklet eltolódását a membránban Proteins are suspended in the inner layer, although the more hydrophilic areas of these proteins "stick out" into the cells interior and outside of the cell. These proteins function as gateways that will, in exchange for a price, allow certain molecules to cross into and out of the cell. These integral proteins are sometimes known as gateway proteins. The outer surface of the membrane will tend to be rich in glycolipids, which have their hydrophobic tails embedded in the hydrophobic region of the membrane and their heads exposed outside the cell. These, along with carbohydrates attached to the integral proteins, are thought to function in the recognition of self.

4 Electron microscopic image of the cell membrane

5 Effects of membrane lipids on ion channel structure and function Biologic membranes are not simply inert physical barriers, but complex and dynamic environments that affect membrane protein structure and function. Residing within these environments, ion channels control the flux of ions across the membrane through conformational changes that allow transient ion flux through a central pore. These conformational changes may be modulated by changes in transmembrane electrochemical potential, the binding of small ligands or other proteins, or changes in the local lipid environment. Ion channels play fundamental roles in cellular function and, in higher eukaryotes, are the primary means of intercellular signaling, especially between excitable cells such as neurons. The focus of this review is to examine how the composition of the bilayer affects ion channel structure and function. This is an important consideration because the bilayer composition varies greatly in different cell types and in different organellar membranes. Even within a membrane, the lipid composition differs between the inner and outer leaflets, and the composition within a given leaflet is both heterogeneous and highly dynamic. Differential packing of lipids (and proteins) leads to the formation of microdomains, and lateral diffusion of these microdomains or "lipid rafts" serve as mobile platforms for the clustering and organization of bilayer constituents including ion channels. The structure and function of these channels are sensitive to specific chemical interactions with neighboring components of the membrane and also to the biophysical properties of their membrane microenvironment (e.g., fluidity, lateral pressure profile, and bilayer thickness). As specific examples, we have focused on the K+ ion channels and the ligand-gated nicotinicoid receptors, two classes of ion channels that have been well-characterized structurally and functionally. The responsiveness of these ion channels to changes in the lipid environment illustrate how ion channels, and more generally, any membrane protein, may be regulated via cellular control of membrane composition

6 Active and Passive Transport Passive transport requires no energy from the cell. Examples include the diffusion of oxygen and carbon dioxide, osmosis of water, and facilitated diffusion. Types of passive transport. Active transport requires the cell to spend energy, usually in the form of ATP. Examples include transport of large molecules (non-lipid soluble) and the sodium-potassium pump.

7 Types of active transport. Carrier-assisted Transport The transport proteins integrated into the cell membrane are often highly selective about the chemicals they allow to cross. Some of these proteins can move materials across the membrane only when assisted by the concentration gradient, a type of carrier-assisted transport known as facilitated diffusion. Both diffusion and facilitated diffusion are driven by the potential energy differences of a concentration gradient. Glucose enters most cells by facilitated diffusion. There seem to be a limiting number of glucosetransporting proteins. The rapid breakdown of glucose in the cell (a process known as glycolysis) maintains the concentration gradient. When the external concentration of glucose increases, however, the glucose transport does not exceed a certain rate, suggesting the limitation on transport. In the case of active transport, the proteins are having to move against the concentration gradient. For example the sodium-potassium pump in nerve cells. Na + is maintained at low concentrations inside the cell and K + is at higher concentrations. The reverse is the case on the outside of the cell. When a nerve message is propagated, the ions pass across the membrane, thus sending the message. After the message has passed, the ions must be actively transported back to their "starting positions" across the membrane. This is analogous to setting up 100 dominoes and then tipping over the first one. To reset them you must pick each one up, again at an energy cost. Up to one-third of the ATP used by a resting animal is used to reset the Na-K pump.

8 Types of transport molecules Uniport transports one solute at a time. Symport transports the solute and a cotransported solute at the same time in the same direction. Antiport transports the solute in (or out) and the co-transported solute the opposite direction. One goes in the other goes out or viceversa. Vesicle-mediated transport Vesicles and vacuoles that fuse with the cell membrane may be utilized to release or transport chemicals out of the cell or to allow them to enter a cell. Exocytosis is the term applied when transport is out of the cell. Endocytosis is the case when a molecule causes the cell membrane to bulge inward, forming a vesicle. Phagocytosis is the type of endocytosis where an entire cell is engulfed. Pinocytosis is when the external fluid is engulfed. Receptor-mediated endocytosis occurs when the material to be transported binds to certain specific molecules in the membrane. Examples include the transport of insulin and cholesterol into animal cells.

9 Sphingomyelin and cholesterol: from membrane biophysics and rafts to potential medical applications. The preferential sphingomyelin-cholesterol interaction which results from the structure and the molecular properties of these two lipids seems to be the physicochemical basis for the formation and maintenance of cholesterol/sphingolipid-enriched nano- and microdomains (referred to as membrane "rafts") in the plane of plasma and other organelle (i.e., Golgi) membranes. This claim is supported by much experimental evidence and also by theoretical considerations. However, although there is a large volume of information about these rafts regarding their lipid and protein composition, their size, and their dynamics, there is still much to be clarified on these issues, as well as on how rafts are formed and maintained. It is well accepted now that the lipid phase of the rafts is the liquid ordered (LO) phase. However, other (non-raft) parts of the membrane may also be in the LO phase. There are indications that the raft LO phase domains are more tightly packed than the non-raft LO phase, possibly due to intermolecular hydrogen bonding involving sphingolipid and cholesterol. This also explains why the former are detergentresistant membranes (DRM), while the non-raft LO phase domains are detergent-soluble (sensitive) membranes (DSM). Recent findings suggest that protein-protein interactions such as cross-linking can be controlled by protein distribution between raft and non-raft domains, and, as well, these interactions affect raft size distribution. The cholesterol/sphingomyelin-enriched rafts seem to be involved in many biological processes, mediated by various receptors, as exemplified by various lipidated glycosylphosphatidylinositol (GPI)- and acyl chain-anchored proteins that reside in the rafts. The rafts serve as signaling platforms in the cell. Various pathogens (viruses and toxins) utilize the raft domains on the host cell membrane as a port of entry, site of assembly (viruses), and port of exit (viral budding). Existence and maintenance of cholesterol-sphingomyelin rafts are dependent on the level of membrane cholesterol and sphingomyelin. This explains why reduction of cholesterol level--either through reverse cholesterol transport, using cholesterol acceptors such as beta-cyclodextrin, or through cholesterol biosynthesis inhibition using statins--interferes with many processes which involve rafts and can be applied to treating raft-related infections and diseases. Detailed elucidation of raft structure and function will improve understanding of biological membrane composition-structure-function relationships and also may serve as a new avenue for the development of novel treatments for major diseases, including viral infections, neurodegenerative diseases (Alzheimer's), atherosclerosis, and tumors.