The cell membrane, also known as plasma membrane, is the membrane surrounding the cytoplasm. The cell membrane forms barrier between the cell and the environment, and also plays important roles in transportation of materials and transmission of signals.

As the cell membrane is too thin to be distinguished from cytoplasm with optical microscope, it took tens of years, after the establishment of cell theory in the 1830s and before the employment of electron microscope in 1950s, to widely convincing people of the existence of cell membrane with several evidence: selective permeability of the living cell shown by Hans Meyer and Ernest Overton independently in the 1890s, dependence of the selective permeability on the surface film of the cell shown by Robert Chambers's microinjection experiment in 1922, impermeablity to ions of the cell boundary evidenced by Rudolf H?ber's electrical measures in the 1910s, and the physical entity of cell membrane demonstrated by Janet Plowe's micromanipulation experiments in 1931.

Under an electron microscope, after stained with water-soluble salts of heavy metals, cell membrane showed a dark-bright-dark three-layered structure. The electron density of the inner and outer layers (2nm each) is higher while the electron density of the intermediate layer (3.5nm) is low. The total thickness of the membrane is about 7.5nm. The three-layered structure called unit membrane. The dark regions are hydrophilic and take up the stains, while the light region is hydrophobic.

Besides the plasma membrane, in eukaryotic cells, there is a lot of intracellular membrane structures such as endoplasmic reticulum, Golgi apparatus, lysosomal membrane, mitochondrial membrane and nuclear membrane. The plasma membrane and intracellular membranes are known as biomembrane collectively.

Mammal erythrocyte membrane, known as red blood cell ghost, is an ideal model for studying the chemical composition of cell membrane, because there is no intracellular membrane that would interfere the purification of cell membrane. The ghost could be obtained by hypotonic treatment that breaks red blood cells and clean out cytoplasmic components, e.g., hemoglobin.

The main compositions of the cell membrane are lipids, proteins and carbohydrates.

Membrane lipids are amphiphilic molecules that have a hydrophilic head (polar end) and a hydrophobic tail (non-polar end). Membrane lipids are classified as phospholipids, cholesterol and Glycolipids.

Phospholipids are the main composition of the membrane, which can be divided into two types, phosphoglycerides and sphingomyelins, based on their structures. Phosphoglyceride consists of a glycerol backbone, two long-chain fatty acids linked to adjacent carbon atoms, and a phosphate group linked to the third carbon atom. The phosphate group in turn is linked to a head group, such as choline, ethanolamine, serine, and inositol. The diversity of the head groups generates a variety of phospholipids. The backbone of sphingomyelin is sphingosine, an 18-carbon acyl chain with an amino group on the 2nd carbon and a hydroxyl group on the 1st and 3rd carbon respectively. In the sphingomyelin, the amino group in turn are attached to a fatty acid chain and the terminal hydroxyl group in turn is attached to a phosphocholine.

Cholesterol molecules stabilize membrane and regulate the fluidity of the membrane.

Glycolipids distribute in the outer side of the plasma membrane. Cerebroside is the simplest glycolipid. It is a major glycolipid in nerve myelin sheath, a multilayered membrane surrounding the axon of some nerve cells, and makes up about 40% of glycolipids. Ganglioside is the most complex glycolipid. It is the most distinctive component of nerve cell membrane and plays an important role in nerve conduction. Gangliosides could serve as the membrane receptors of cholera toxin, tetanus toxin and interferon. For example, cholera toxin can bind to ganglioside GM1 on intestinal epithelial cells and enter cells, which causes diarrhea.

In aqueous solution, phospholipid molecules automatically aggregate to expose the hydrophilic polar heads to water and hide the nonpolar hydrophobic tails in the interior, which may results in either spherical micelles with heads outward and tails inward or lipid bilayers with hydrophobic tails sandwiched between the heads.

Liposome is a sealed compartment formed by the spontaneous closure of a lipid bilayer. It can embed a variety of substances.

Liposomes could be used to embed DNA fragments and transfer them into target cells via fusion with the cell membrane.

Liposomes could be used to embed medicines such as heparin and insulin that are instable or hard to be absorbed. Liposome embedding can significantly increase medicine's stability, delay their releasing, prolong the duration of effect, maintain relatively stable blood concentration of the medicine, and thereby enhance the efficacy of medicines. Liposome embedding of antineoplastic drugs may increase their specificity to tumor cells and reduce the toxicity to normal cells.

Membrane proteins are the proteins associated with biological membranes. Membrane proteins perform most of the function of the membranes and specify various functions of different membranes, such as connection, supporting, transportation, cell recognition, signal transduction. Membrane proteins could be classified as intrinsic and extrinsic.

Intrinsic proteins, also known as integral proteins and transmembrane proteins, are amphiphilic molecules with hydrophilic regions exposed outside of the membrane and hydrophobic region(s) buried in lipid bilayer and interacting with the hydrophobic tails of membrane lipid molecules via hydrophobic and/or hydrogen bonds. To isolate and purify these proteins, detergent such as sodium dodecyl sulfate (SDS) and Triton, or other strenuous conditions including ultrasonic treatment, is required to break down cell. Intrinsic proteins may be integrated to the membrane with a single-pass α-helix, multiple-pass α-helices or beta barrel formed by twisting and coiling of a large beta-sheet.

Extrinsic membrane proteins, also known as peripheral proteins, locate on the inner or outer side of the cell membrane without any part extending across the lipid bilayer. They are associated with cell membrane by an amphiphilic α helix integrated in the cytosolic monolayer of the membrane, a covalently bound lipid chain inserted in the cytosolic lipid monolayer, an oligosaccharide linked to phosphatidylinositol in the noncytosolic monolayer or attached to the membrane by noncovalent interactions with other membrane proteins. Extrinsic membrane proteins associate with the membrane much weaker and are much easier to be isolated. Mild treatments such as altering ion concentration, altering the pH value and adding chelating agent can dissociate extrinsic membrane proteins from the membrane.

Membrane carbohydrates, oligosaccharide chains covalently linked to membrane lipids or membrane proteins, namely glycolipids and glycoproteins, covers the surface of non-cytosolic side of cell membrane. The oligosaccharide chains usually consist of 1-10 monosaccharides or monosaccharide derivatives. There are seven major types of oligosaccharide units, glucose, galactose, mannose, fucose, galactosamine, glucosamine and sialic acid.

The sequence of membrane carbohydrate serve as a flag of the cells and play a role in cell recognition. The antigen that specify the ABC blood types are membrane carbohydrates on red blood cell membrane. Membrane carbohydrates can also form a coat on the cell surface and protect the cell.

The types and quantities of the molecules of the inner and outer layers of cell membrane are different, which results in distinct functions of the two sides of cell membrane and polarity of cell membrane function.

Asymmetrical Distribution of Membrane Lipids. As shown in red cell membrane, choline-containing phospholipids such as phosphatidylcholine and sphingomyelin mainly distribute in the outer lipid layer while amino-phospholipids such as phosphatidylserine, phosphatidylinositol and phosphatidylethanolamine mainly distribute in inner lipid layer.

Asymmetrical Distribution of Membrane Proteins. Distribution of membrane proteins is absolutely asymmetrical. The types, quantities and locations of proteins are asymmetrical. Receptors receive signals outside, while enzymes catalyze reactions inside. The two hydrophilic domains of a transmembrane protein vary in length and sequence of amino acids. With frozen fracture electron microscopy, the distribution difference of inner and outer membrane proteins is obvious.

Asymmetrical Distribution of Membrane Carbohydrates. Glycolipids and glycoproteins are located on the non-cytosolic surface of cell membrane.

Cell membrane asymmetry is also revealed by the lipid rafts, the microdomains rich in cholesterol and sphingomyelin. Lipid rafts are docking platforms for protein, which is conducive to protein conformation and involved in signal transduction, receptor-mediated endocytosis and cholesterol metabolism.

Membrane fluidity refers to the viscosity of cell membrane. A membrane with higher fluidity is less viscous. The fluidity of cell membrane comes from the motility of membrane lipid molecules and membrane protein molecules.

Cell membrane is in liquid crystal state, i.e., its molecules are arranged in a crystal-like manner, but it may flow like a liquid. Under normal physiological temperature, lipid molecules are in constant thermal motion. When the temperature dropped below a critical point, the membrane became crystal, on the contrary, when the temperature rose above the critical point, the membrane melted into liquid crystal. The state transition is called phase transition, and the critical temperature is called phase transition temperature. Above the phase transition temperature, the liquid molecules are always in motion. There are six motion types of membrane lipid molecules:

Lateral Movement. Lipid molecules rapidly exchange positions with their neighbors in the same monolayer.

Rotary Motion. Lipid molecules rotate rapidly on their long axis.

Flip-flop. Lipid molecules migrate from exoplasmic side (flip) or cytoplasmic side (flop) to the other side. Flip-flop is very rare in protein-free membrane for any lipid molecule except cholesterol that can flip-flop rapidly. Flip-flop could be promoted by proteins called phospholipid translocators, namely, flippase, floppase and scramblase.

Flexion. The fatty acid chains of the lipids can swing.

Shocking. The fatty acid chains of the lipids shock themselves.

Intramolecular Rotation. Fatty acid chains rotate around their C-C bonds and generate conformational isomers.

Membrane proteins can undergo lateral movements and rotary motions that rotate around the axis perpendicular to the membrane plane.

Membrane fluidity is determined by its composition.

The degree of fatty acid unsaturation. The bend at the cis double bond of unsaturated fatty acid chains interferes with ordered packing of fatty acyl chains, diminishes the phase transition temperature of cell membrane and increases the fluidity. The more unsaturated bonds the membrane contain, the greater the membrane fluidity is.

Length of fatty acid chain. The longer the fatty acid chains are, the tighter they interact with each other, and thus the lower the membrane fluidity is. The shorter the fatty acid chains are, the weaker they interact with each other, and thus the higher the membrane fluidity is.

Cholesterol level. Above the phase transition temperature, cholesterol molecules increase the orderliness of membrane lipid molecules. Because cholesterol molecules can inhibit the movement of fatty acid chain, reduce their distortions, and reduce the fluidity of the membrane. Below the phase transition temperature, the membrane is in the crystalline state, cholesterol can effectively prevent fatty acid chains of phospholipid molecules from mutual aggregating and prevent membrane fluidity drop severely with the dropping temperature. Cholesterol has two-way regulating functions on membrane fluidity.

Ratio of lecithin and sphingomyelin. Lecithin contains high level unsaturated fatty acids and decreases the phase transition temperature. Sphingomyelinase contains low level unsaturated fatty acids and increases the phase transition temperature. Sphingomyelin's viscosity is 6 times greater than lecithin's, so the higher the lecithin/sphingomyelin ratio is, the greater the membrane fluidity is. In the membrane of aging cells and atherosclerosis cells, the lecithin/sphingomyelin ratio is decreased and thus the fluidity of the cell membrane is decreased.

Membrane Proteins. The more intrinsic proteins there is in the lipid bilayer, the lower the membrane fluidity is.

Historically, the liquid mosaic model, proposed by Seymour Jonathan Singer and Garth L. Nicolson in 1972, is the most widely accepted model of the structure of cell membranes. The main points of this model are:

1. Phospholipids form the bilayer matrix

2. Proteins and glycoproteins are integral or attached to the matrix

3. The lipid bilayer is fluid and the proteins are mobile

The lipid raft model proposes that the lipid bilayer is not homogeneous, but the fluctuating lipid assemblies, called rafts, dynamically compartmentalize the membrane. The rafts are composed of sphingolipids, cholesterol and proteins and serve as platforms for membrane signaling and trafficking.

The lipid bilayer of cell membrane has a hydrophobic interior. The membrane transport of small molecules and ions has the following characteristics:

1. The smaller the molecule is, the more easily it gets across the membrane.

2. The more lipid-soluble molecule is, the more easily it gets across the lipid bilayer.

3. The lower the polarity of the molecule, the more rapidly it gets across the lipid bilayer.

4. Uncharged molecule gets across the membrane more easily.

5. It is very hard for charged molecules to diffuse across the membrane. The hydration shell of an ion increases its volume and further prevents its diffusion.

Passive transport is a movement of small molecules and ions across the membrane without consuming cellular metabolic energy.

Simple diffusion is the way for oil soluble, nonpolar or uncharged small molecules to traverse the cell membrane from higher concentration side to lower concentration side without consuming cellular metabolic energy and without the assistance from membrane transport protein.

Materials Traversing Cell Membrane by Simple Diffusion includes lipid-soluble materials (e.g., hormone, lipophilic vitamin, benzene, O2, N2) and uncharged polar molecules (e.g., urea, glycerol, alcohol, ether, H2O, CO2, CO).

Facilitated diffusion is the way for lipophobic, charged or polar molecules and ions to traverse membrane down their concentration gradient without consuming cellular metabolic energy but with the assistance from membrane transport proteins, i.e., channel proteins or carrier proteins.

A channel protein is integral membrane protein that forms hydrophilic pore to mediate water or specific solutes across the membrane. It can transport materials much faster. It is highly selective to the size and electric charge of ions. Although theoretically the transport rate will always increase with the concentration of the solutes, the transport rate is saturable as the number of channel proteins in the membrane is limited. The channels may be either continuously or discontinuously open. It mediates passive transport only. There are several types of channel proteins: aquaporins, ion channels, and carrier proteins.

Aquaporins (AQPs) are a family of channel proteins that primarily conduct water across the membrane. AQPs are divided into two subfamilies, orthodox aquaporins that only conduct water and aquaglyceroporins that could additionally conduct other small molecules such as glycerol, urea, nitrate, and metalloids arsenite. The water selectivity of an orthodox AQP is enabled by the size of the pore and the positive charge of some gating residues. AQPs cannot function as water pump but only speed up the movement of water. Without AQP, water traverses membrane very slowly by simple diffusion. With AQP, water traverses membrane rapidly by facilitated diffusion.

Ion channels are the channel proteins selective for inorganic ions. The channel facilitated diffusion is up to 1,000 times faster than transporter mediated transport. An open channel can pass 107-108 ion through per second. Ion channels can be classified into several types according to the controlling mechanisms:

Non-gated ion channels remain open at all time. The passive transmembrane movement of ions at rest state of neurons takes place via non-gated channel.

The phosphorylation-gated ion channels are open when they are phosphorylated.

The ligand-gated ion channels are open when specific ligands bind to them. For example, the nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are composed of five subunits symmetrically arranged. When the extracellular regions bind to acetylcholine, the conformation of the channel changes and the ions can flow into the cell quickly. The channel is open for only a very short time and the ligands dissociate from the receptor very quickly, after which the channel restores its original conformation and gets closed immediately.

The voltage-gated ion channels are open by changes in the electrical membrane potential nearby. In resting state, the extracellular solution contains more Na+ and Cl+ while the intracellular fluid contains more K+, which give rise to the electrical potential difference across the cell membrane. When there is a sudden change of the membrane potential, the nearby voltage-gated channel is transiently open and becomes permeable for Na+. The influx of Na+ then is stopped rapidly when the inactivation peptide occludes the open pore and inactivates the channel.

Mechanosensitive ion channels, also known as stretch-gated ion channels, are responsive to mechanical stimuli such as pressure, shear stress, and osmotic concentration. For example, inner ear hair cells sense the acoustic signal with mechanosensitive ion channels.

Carrier proteins, or carriers, are integral membrane proteins that move specific substance across cellular membranes. Carriers are more specific than channels. The carrier proteins translocate a limited number of molecules across the membrane by each conformational change, which is different from the channels that could serve for a large number of molecules flux through once open. There are three type of carriers, the uniporters that transport a single substance down its concentration gradient, the symporters that transport two or more substrates with at list one of them down its concentration gradient, and antiporters that transport two substrates in opposite direction with one of them down its concentration gradient. Carrier proteins are more specific than ion channels but much slower. They are saturable. When all the carriers are in use, the transport speed reach its maximum. Some carrier proteins mediate active transport.

Facilitative glucose transporters (GLUTs) are the carriers that facilitate glucose flux through the membrane from the higher-concentration side to the lower-concentration side. Binding with glucose changes the conformation of a GLUTs and the glucose gets transported.

Active transport is transmembrane transport of small molecules and ions up concentration gradient with carrier protein consuming cell metabolic energy.

This type of ion pumps use energy from adenosine triphosphate (ATP) to move ions across membranes, and thus they are ATPases. The pumps is very specific and much slower than carriers and channels. As the pumping process is reversible and the pumps could also synthesis ATP when the concentration of ATP is low enough, they are also ATP synthases.

Sodium-Potassium Pumps (Na+/K+ Pumps). A Na+/K+ pump, also named Na+/K+-ATPase, is found in all animal cells. It pumps Na+ out of cells while pumps K+ into cells. After binding a molecule of ATP, the pump binds three Na+, after which the ATP is hydrolyzed and the pump is phosphorylated. The phosphorylation changes the conformation of the pump and three Na+ were released outside and two K+ bind to the pump. The binding of K+ dephosphorylates the pump and changes the conformation the pump, which results in releasing K+ into the cell. Thus, at each pumping cycle, three Na+ get out of and two K+ get into the cell and one ATP molecule is hydrolyzed. The pump could act as much as 8000 times per minute. In some neurons, the Na+/K+ pumps may consume as much as 2/3 of the total energy expenditure. The Na+/K+ pump plays an important role in maintaining the membrane potential, supplying ion gradient for secondary active transporters, and controlling cell volume.

Calcium (Ca2+) pumps. A Ca2+ pump, also named Ca2+-ATPase, plays an important role in Ca2+ signaling. The Ca2+ pumps maintain low cytosol Ca2+ concentration at rest by moving Ca2+ against its electrochemical gradient to endoplasmic reticulum, Golgi apparatus, secretory vesicles or extracellular environment. Ca2+ pumps are categorized to three multigene families, endoplasmic reticulum (SERCA), plasma membrane (PMCA) and secretory pathway Ca2+ ATPase (SPCA) pumps. One acting cycle of the pumps could move one (PMCA or SPCA pumps) or two (SERCA pumps) Ca2+ and breaks down one ATP. The SERCA and, possibly, PMCA pumps also transport of H+ in the opposite direction at each acting cycle. When a muscle cell is excited, a great amount of Ca2+ flux from the sarcoplasmic reticulum into the cytosol rapidly, in milliseconds, via voltage-gated Ca2+ channels and power the Ca2+ dependent contractile proteins to drive muscle contraction. After the contraction, the Ca2+ are transported to sarcoplasmic reticulum by SERCA pumps.

V-ATPase. Vacuolar-type H+-ATPase, also known as V-ATPase, pumps H+ across the cellular membranes against its concentration gradient in an ATP-driven manner, which is required for keeping low-pH environment of the membrane-bound compartments such as lysosome and endosome.

The cotransporters, i.e., symporters and antiporters, transport ions and small molecules, such as glucose and amino acids, with the energy stored in electrochemical gradient of ions, such as Na+ and H+. The electrochemical gradient is generated and maintained by ion pumps. All the cotransport processes are reversible and the direction of the net cross-membrane transfer of the substrates is determined by the substrate concentrations.

Symporters. In animal cells, symporters are mainly driven by the Na+ concentration gradient maintained by Na+/K+ ATPase. Small intestine epithelium cells (enterocytes) absorb nutrient substance, such as glucose, galactose, mannose and amino acids, partially with symporters. For example, sodium-dependent glucose cotransporters 1 (SGTL1) on the brush border membrane (BBM) transport glucose and galactose, along with Na+, into the enterocyte from the lumen and the Glucose transporter 2 (GLUT2) on the basolateral membrane (BLM) facilitates the diffusing of glucose, galactose and fructose from the enterocyte into the blood. The Na+ were pumped into the blood from the enterocyte by Na+/K+ ATPase so that the gradient of Na+ is maintained. The Fructose diffuses across BBM into the enterocytes by facilitative diffusion via GLUT5.

Antiporters. Na+/H+ antiporters, also called Na+/H+ exchangers, are ubiquitous antiporters transporting Na+ and H+ in opposite direction across the cell membrane and thus play a role in regulation of cell pH value. Na+/Ca2+ antiporters, also called Na+/Ca2+ exchangers, exchange Na+ and Ca2+ across the cell membrane, which play important role in removing cytosolic Ca2+ after contraction of the muscle.

Macromolecules and large particles could be taken up by a distinct process called endocytosis, in which the substance is surrounded by an area of the cell membrane budding into the cell to form a vesicle. The reverse process of endocytosis is exocytosis, in which the substance is enclosed in a membrane vesicle that is then fused to the cell membrane and gets the content released. Both of endocytosis and exocytosis are active transport processes.

Based on the mode of uptake and the intracellular fate of the substance uptake, endocytosis processes could be categorized as phagocytosis, pinocytosis, and receptor-mediated endocytosis.

Phagocytosis is the process of engulfment of larger solid particles with diameters greater than 250nm. During phagocytosis, a cell extend its cell membrane surrounding the particle, which engulfs the particle and, when enclosed, forms an internal vesicle called phagosome. The phagosome then fuses to the lysosome and forms a phagolysosome to degrade the ingested material. The engulfment of the particle is promoted by actin-myosin contracting, which could be inhibited by cytochalasins, the fungal metabolites that could bind to actin filament and block the elongation of actin filaments.

Phagocytosis is the main process to ingest food for unicellular protozoa such as amoeba and paramecium. In higher mammals including humans, only a few cell types are phagocytic, e.g., WBCs engulf bacteria, macrophages clean up aging red blood cells and cell debris.

Pinocytosis, also known as cell drinking, is the process taking up liquid unspecifically via extending membrane that eventually forms intracellular vesicle.

The majority of pinocytosis vesicles are endocytotic and fuse with lysosomes in the cell to get the ingested material digested with the lysosomal enzymes.

Some pinocytotic vesicles are transcytotic. They do not fuse with lysosomes but fuse with the opposite cell membrane. Such a process is called transcytosis.

In receptor-mediated endocytosis, cells take up receptors and their ligands with small pits that eventually forms endocytic vesicles. The vesicles are mainly coated with clathrin and thus the receptor-mediated endocytosis is also called clathrin-mediated endocytosis. Receptor-mediated endocytosis is a selective concentrating mechanism that the cells can absorb specific macromolecules in very low extracellular concentration. Receptor-mediated endocytosis is much faster than many other endocytosis forms. For example, the fetus takes up maternal antibodies and a cell intakes cholesterol via receptor-mediated endocytosis.

A clathrin molecule is composed of three bending heavy chains and three light chains. The three heavy chains join together near their C-terminal ends to form three-limbed shape that is called triskelion. Each heavy chain has a light chain bound near the join. In vitro, the clathrin triskelion can form cages independently at pH < 6.5 and with presence of adapter protein at neutral pH. A clathrin cage may be composed by tens to hundreds of clathrin molecules.

Endocytosis of cholesterol. Blood cholesterol is in low density lipoprotein (LDL) particles, which could be taken up by peripheral cells with LDL receptors (LDLRs) integrated in the cell membrane. During the endocytosis, a LDL binds to the LDLRs, and clathrin molecules are recruited by the adaptor protein and bind to the tail of the receptor to form a pit. The pit is internalized to be a clathrin-coated vesicle. The vesicle then loses its coat and then fuses with early endosome. The early endosome mature gradually into late endosome while fusing with other early endosomes or late endosomes. The ATP-driven H+ pumps keep the late endosome acidic inside. The LDL dissociates for LDLRs in low pH (~5.0) environment of the late endosome. The LDLRs are recycled to the cell membrane with the vesicle budding off the endosome while the LDL is delivered to lysosome. In the lysosome, the LDL is degraded and free cholesterol is released from the endolysosomal system. The cholesterol is delivered to cellular membranes such as cell membrane, endoplasmic reticulum, endosomes and mitochondria.

Endocytosis of Ferric Iron. Ferric Iron (Fe3+) was transported with transferrin in the body from liver or intestine to all tissues. Cells take up Fe3+ in a manner similar to that of LDL but with some difference. Two atoms of Fe3+ bind to the transferrin dimer, called apotransferrin when not bound to Fe3+, to form ferro-transferrin, which then binds to the transferrin receptor integrated in the cell membrane. Then the adaptor protein binds to the receptor tail and the clathrin bind to the adaptor, which pits the cell membrane and eventually results in endocytic clathrin-coated vesicle. Then the vesicle gets its coat shed and fuses to endosome. In the acidic late endosome, the Fe3+ is released from the receptor-ferro-transferrin complex. Then the apotransferrin is recycled to the cell membrane with the receptor, via a process called exocytosis. After released from the receptor in the neutral environment, e.g. blood, the Fe3+ ions are reduced to Fe2+ ions and then exported into the cytosol by ion transporter.

Exocytosis is the process by which a cell may release substance such as enzymes, hormones, and wastes by enclosing it in a membrane vesicle that moves to and fuses with the cell membrane. Exocytosis is an active transport and consumes ATP. It is also employed to transport or recycle lipids and membrane proteins including receptors to cell membrane.

The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins target the vesicle to the cell membrane and drive the fusion at specific site. The SNAREs are a family of transmembrane proteins on both transport vesicle (v-SNAREs) and target cell membrane (t-SNAREs). The t-SNARE form a binary complex with SNAP (soluble N-ethylmaleimide-sensitive factor attachment protein). When v-SNARE meet t-SNARE, they could assemble into an alpha-helical bundle, which pull the membranes together. The assembly of SNAREs is triggered by Ca2+ and regulated by other proteins. After the membranes fuse, SNAPs recruit NSF (N-ethylmaleimide sensitive factor) to disassemble the SNARE complex and recycle the SNAREs.

Constitutive Exocytosis Pathway. In all eukaryotic cells, newly synthesized lipids and proteins are transport to cell membrane by exocytosis process without signal stimuli. This constitutive exocytosis pathway enables the cell membrane to enlarge or refresh.

Regulated Exocytosis Pathway. Regulated exocytosis pathway operates only in cells specialized for secretion. The secretory vesicles with particular substance, such as hormone, digestive enzymes and neurotransmitters, accumulate near the plasma membrane, where they wait for signal. A signal may open the ion channels for Ca2+ to flux into the cell and triggers the assembling of v-SNARE and t-SNARE.

Channelopathies are diseases caused by disfunction of ion channels, which could be caused by gene mutations of the proteins consisting or regulating an ion channel, or by autoimmune attack on an ion channel. Cystic fibrosis (CF), an autosomal recessive disease, is caused by mutation of the gene coding cystic fibrosis transmembrane regulator (CFTR), a chloride (Cl-) channel protein in endothelial cells of air duct, digestive tract and genital tract. CFTR defects impede the flow of Cl- and H2O, which results in health problems, such as buildup of thick mucus in the lung, frequent lung infection, salty sweat, and fatty stool.

Cystinuria, an autosomal recessive disease, is caused by mutations in genes coding SLC3A1 and SLC7A9. These two proteins are components of the renal amino acid transporter that reabsorbs neutral and basic amino acids such as cysteine, lysine, ornithine and arginine. Defects in either SLC3A1 or SLC7A9 result in an excessive concentration of cysteine and, in severe cases, forming of cysteine crystals in the urine.

Familial renal glycosuria, an autosomal disorder, is rare and usually caused by the defects of SGLT2. SGLT2 is a sodium-dependent glucose cotransporter reabsorbs glucose in the renal proximal tubule. Defects of SGLT2 result in excretion of glucose in urine under normal even low blood glucose level.

Familial hypercholesterolemia (FH) is a genetic disorder featured by very high LDL levels in the blood. LDLR defects is the most common genetic causes of FH. LDLR defects imped the clearance of LDL from the blood. The high cholesterol deposition at artery wall leads to atherosclerosis, which causes cardiovascular disease.

Myasthenia gravis (MG) is an autoimmune disease that results from antibodies targeting nicotinic acetylcholine receptor (nAchR) at the neuromuscular junction. The blocking or destroying of nAchR prevents the exciting of muscle and thus the muscle does not contract to output force.

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