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Cell membrane
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Cell membrane
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Illustration of a eukaryotic cell membrane
Comparison of a eukaryote and a prokaryote.

The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a semipermeable biological membrane that separates and protects the interior of a cell from the outside environment (the extracellular space).[1][2] The cell membrane is a lipid bilayer, usually consisting of phospholipids and glycolipids; eukaryotes and some archaea typically have sterols (such as cholesterol in animals) interspersed between them as well, maintaining appropriate membrane fluidity at various temperatures. The membrane also contains membrane proteins, including integral proteins that span the membrane and serve as transporters, and peripheral proteins that attach to the surface of the cell membrane, acting as enzymes to facilitate interaction with the cell's environment.[3] Glycolipids embedded in the outer lipid layer serve a similar purpose.

The cell membrane controls the movement of substances in and out of a cell, being selectively permeable to ions and organic molecules.[4] In addition, cell membranes are involved in a variety of cellular processes such as cell adhesion, ion conductivity, and cell signaling and serve as the attachment surface for several extracellular structures, including the cell wall and the carbohydrate cell coat called the glycocalyx, as well as the intracellular network of protein fibers called the cytoskeleton. In the field of synthetic biology, cell membranes can be artificially reassembled.[5][6][7][8]

History

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Main article: History of cell membrane theory

Robert Hooke's discovery of cells in 1665 led to the proposal of the cell theory. Initially it was believed that all cells contained a hard cell wall since only plant cells could be observed at the time.[9] Microscopists focused on the cell wall for well over 150 years until advances in microscopy were made. In the early 19th century, cells were recognized as being separate entities, unconnected, and bound by individual cell walls after it was found that plant cells could be separated. This theory extended to include animal cells to suggest a universal mechanism for cell protection and development.

By the second half of the 19th century, microscopy was still not advanced enough to make a distinction between cell membranes and cell walls. However, some microscopists correctly identified at this time that while invisible, it could be inferred that cell membranes existed in animal cells due to intracellular movement of components internally but not externally and that membranes were not the equivalent of a plant cell wall. It was also inferred that cell membranes were not vital components to all cells. Many refuted the existence of a cell membrane still towards the end of the 19th century. In 1890, a revision to the cell theory stated that cell membranes existed, but were merely secondary structures. It was not until later studies with osmosis and permeability that cell membranes gained more recognition.[9] In 1895, Ernest Overton proposed that cell membranes were made of lipids.[10]

The lipid bilayer hypothesis, proposed in 1925 by Gorter and Grendel,[11] created speculation in the description of the cell membrane bilayer structure based on crystallographic studies and soap bubble observations. In an attempt to accept or reject the hypothesis, researchers measured membrane thickness. These researchers extracted the lipid from human red blood cells and measured the amount of surface area the lipid would cover when spread over the surface of the water. Since mature mammalian red blood cells lack both nuclei and cytoplasmic organelles, the plasma membrane is the only lipid-containing structure in the cell. Consequently, all of the lipids extracted from the cells can be assumed to have resided in the cells' plasma membranes. The ratio of the surface area of water covered by the extracted lipid to the surface area calculated for the red blood cells from which the lipid was 2:1(approx) and they concluded that the plasma membrane contains a lipid bilayer.[9][12]

In 1925 it was determined by Fricke that the thickness of erythrocyte and yeast cell membranes ranged between 3.3 and 4 nm, a thickness compatible with a lipid monolayer. The choice of the dielectric constant used in these studies was called into question but future tests could not disprove the results of the initial experiment. Independently, the leptoscope was invented in order to measure very thin membranes by comparing the intensity of light reflected from a sample to the intensity of a membrane standard of known thickness. The instrument could resolve thicknesses that depended on pH measurements and the presence of membrane proteins that ranged from 8.6 to 23.2 nm, with the lower measurements supporting the lipid bilayer hypothesis. Later in the 1930s, the membrane structure model developed in general agreement to be the paucimolecular model of Davson and Danielli (1935). This model was based on studies of surface tension between oils and echinoderm eggs. Since the surface tension values appeared to be much lower than would be expected for an oil–water interface, it was assumed that some substance was responsible for lowering the interfacial tensions in the surface of cells. It was suggested that a lipid bilayer was in between two thin protein layers. The paucimolecular model immediately became popular and it dominated cell membrane studies for the following 30 years, until it became rivaled by the fluid mosaic model of Singer and Nicolson (1972).[13][9]

Despite the numerous models of the cell membrane proposed prior to the fluid mosaic model, it remains the primary archetype for the cell membrane long after its inception in the 1970s.[9] Although the fluid mosaic model has been modernized to detail contemporary discoveries, the basics have remained constant: the membrane is a lipid bilayer composed of hydrophilic exterior heads and a hydrophobic interior where proteins can interact with hydrophilic heads through polar interactions, but proteins that span the bilayer fully or partially have hydrophobic amino acids that interact with the non-polar lipid interior. The fluid mosaic model not only provided an accurate representation of membrane mechanics, it enhanced the study of hydrophobic forces, which would later develop into an essential descriptive limitation to describe biological macromolecules.[9]

For many centuries, the scientists cited disagreed with the significance of the structure they were seeing as the cell membrane. For almost two centuries, the membranes were seen but mostly disregarded as an important structure with cellular function. It was not until the 20th century that the significance of the cell membrane as it was acknowledged. Finally, two scientists Gorter and Grendel (1925) made the discovery that the membrane is "lipid-based". From this, they furthered the idea that this structure would have to be in a formation that mimicked layers. Once studied further, it was found by comparing the sum of the cell surfaces and the surfaces of the lipids, a 2:1 ratio was estimated; thus, providing the first basis of the bilayer structure known today. This discovery initiated many new studies that arose globally within various fields of scientific studies, confirming that the structure and functions of the cell membrane are widely accepted.[9]

The structure has been variously referred to by different writers as the ectoplast (de Vries, 1885),[14] Plasmahaut (plasma skin, Pfeffer, 1877, 1891),[15] Hautschicht (skin layer, Pfeffer, 1886; used with a different meaning by Hofmeister, 1867), plasmatic membrane (Pfeffer, 1900),[16] plasma membrane, cytoplasmic membrane, cell envelope and cell membrane.[17][18] Some authors who did not believe that there was a functional permeable boundary at the surface of the cell preferred to use the term plasmalemma (coined by Mast, 1924) for the external region of the cell.[19][20][21]

Composition

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Cell membranes contain a variety of biological molecules, notably lipids and proteins. Composition is not set, but constantly changing for fluidity and changes in the environment, even fluctuating during different stages of cell development. Specifically, the amount of cholesterol in human primary neuron cell membrane changes, and this change in composition affects fluidity throughout development stages.[22]

Material is incorporated into the membrane, or deleted from it, by a variety of mechanisms:

  • Fusion of intracellular vesicles with the membrane (exocytosis) not only excretes the contents of the vesicle but also incorporates the vesicle membrane's components into the cell membrane. The membrane may form blebs around extracellular material that pinch off to become vesicles (endocytosis).
  • If a membrane is continuous with a tubular structure made of membrane material, then material from the tube can be drawn into the membrane continuously.
  • Although the concentration of membrane components in the aqueous phase is low (stable membrane components have low solubility in water), there is an exchange of molecules between the lipid and aqueous phases.

Lipids

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Examples of the major membrane phospholipids and glycolipids: phosphatidylcholine (PtdCho), phosphatidylethanolamine (PtdEtn), phosphatidylinositol (PtdIns), phosphatidylserine (PtdSer).

The cell membrane consists of three classes of amphipathic lipids: phospholipids, glycolipids, and sterols. The amount of each depends upon the type of cell, but in the majority of cases phospholipids are the most abundant, often contributing for over 50% of all lipids in plasma membranes.[23][24] Glycolipids only account for a minute amount of about 2% and sterols make up the rest. In red blood cell studies, 30% of the plasma membrane is lipid. However, for the majority of eukaryotic cells, the composition of plasma membranes is about half lipids and half proteins by weight.

The fatty chains in phospholipids and glycolipids usually contain an even number of carbon atoms, typically between 16 and 20. The 16- and 18-carbon fatty acids are the most common. Fatty acids may be saturated or unsaturated, with the configuration of the double bonds nearly always "cis". The length and the degree of unsaturation of fatty acid chains have a profound effect on membrane fluidity as unsaturated lipids create a kink, preventing the fatty acids from packing together as tightly, thus decreasing the melting temperature (increasing the fluidity) of the membrane.[23][24] The ability of some organisms to regulate the fluidity of their cell membranes by altering lipid composition is called homeoviscous adaptation.

The entire membrane is held together via non-covalent interaction of hydrophobic tails, however the structure is quite fluid and not fixed rigidly in place. Under physiological conditions phospholipid molecules in the cell membrane are in the liquid crystalline state. It means the lipid molecules are free to diffuse and exhibit rapid lateral diffusion along the layer in which they are present.[23] However, the exchange of phospholipid molecules between intracellular and extracellular leaflets of the bilayer is a very slow process. Lipid rafts and caveolae are examples of cholesterol-enriched microdomains in the cell membrane.[24] Also, a fraction of the lipid in direct contact with integral membrane proteins, which is tightly bound to the protein surface is called annular lipid shell; it behaves as a part of protein complex.

Cholesterol is normally found dispersed in varying degrees throughout cell membranes, in the irregular spaces between the hydrophobic tails of the membrane lipids, where it confers a stiffening and strengthening effect on the membrane.[4] Additionally, the amount of cholesterol in biological membranes varies between organisms, cell types, and even in individual cells. Cholesterol, a major component of plasma membranes, regulates the fluidity of the overall membrane, meaning that cholesterol controls the amount of movement of the various cell membrane components based on its concentrations.[4] In high temperatures, cholesterol inhibits the movement of phospholipid fatty acid chains, causing a reduced permeability to small molecules and reduced membrane fluidity. The opposite is true for the role of cholesterol in cooler temperatures. Cholesterol production, and thus concentration, is up-regulated (increased) in response to cold temperature. At cold temperatures, cholesterol interferes with fatty acid chain interactions. Acting as antifreeze, cholesterol maintains the fluidity of the membrane. Cholesterol is more abundant in cold-weather animals than warm-weather animals. In plants, which lack cholesterol, related compounds called sterols perform the same function as cholesterol.[4]

Phospholipids forming lipid vesicles

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Lipid vesicles or liposomes are approximately spherical pockets that are enclosed by a lipid bilayer.[25] These structures are used in laboratories to study the effects of chemicals in cells by delivering these chemicals directly to the cell, as well as getting more insight into cell membrane permeability. Lipid vesicles and liposomes are formed by first suspending a lipid in an aqueous solution then agitating the mixture through sonication, resulting in a vesicle. Measuring the rate of efflux from the inside of the vesicle to the ambient solution allows researchers to better understand membrane permeability.[citation needed] Vesicles can be formed with molecules and ions inside the vesicle by forming the vesicle with the desired molecule or ion present in the solution. Proteins can also be embedded into the membrane through solubilizing the desired proteins in the presence of detergents and attaching them to the phospholipids in which the liposome is formed.[citation needed] These provide researchers with a tool to examine various membrane protein functions.

Carbohydrates

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Plasma membranes also contain carbohydrates, predominantly glycoproteins, but with some glycolipids (cerebrosides and gangliosides). Carbohydrates are important in the role of cell-cell recognition in eukaryotes; they are located on the surface of the cell where they recognize host cells and share information. Viruses that bind to cells using these receptors cause an infection.[26] For the most part, no glycosylation occurs on membranes within the cell; rather generally glycosylation occurs on the extracellular surface of the plasma membrane. The glycocalyx is an important feature in all cells, especially epithelia with microvilli. Recent data suggest the glycocalyx participates in cell adhesion, lymphocyte homing,[26] and many others. The penultimate sugar is galactose and the terminal sugar is sialic acid, as the sugar backbone is modified in the Golgi apparatus. Sialic acid carries a negative charge, providing an external barrier to charged particles.

Proteins

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Type Description Examples
Integral proteins
or transmembrane proteins		 Span the membrane and have a hydrophilic cytosolic domain, which interacts with internal molecules, a hydrophobic membrane-spanning domain that anchors it within the cell membrane, and a hydrophilic extracellular domain that interacts with external molecules. The hydrophobic domain consists of one, multiple, or a combination of α-helices and β sheet protein motifs. Ion channels, proton pumps, G protein-coupled receptor
Lipid anchored proteins Covalently bound to single or multiple lipid molecules; hydrophobically insert into the cell membrane and anchor the protein. The protein itself is not in contact with the membrane. G proteins
Peripheral proteins Attached to integral membrane proteins, or associated with peripheral regions of the lipid bilayer. These proteins tend to have only temporary interactions with biological membranes, and once reacted, the molecule dissociates to carry on its work in the cytoplasm. Some enzymes, some hormones

The cell membrane has large content of proteins, typically around 50% of membrane volume[27] These proteins are important for the cell because they are responsible for various biological activities. Approximately a third of the genes in yeast code specifically for them, and this number is even higher in multicellular organisms.[25] Membrane proteins consist of three main types: integral proteins, peripheral proteins, and lipid-anchored proteins.[4]

As shown in the adjacent table, integral proteins are amphipathic transmembrane proteins. Examples of integral proteins include ion channels, proton pumps, and g-protein coupled receptors. Ion channels allow inorganic ions such as sodium, potassium, calcium, or chlorine to diffuse down their electrochemical gradient across the lipid bilayer through hydrophilic pores across the membrane. The electrical behavior of cells (i.e. nerve cells) is controlled by ion channels.[4] Proton pumps are protein pumps that are embedded in the lipid bilayer that allow protons to travel through the membrane by transferring from one amino acid side chain to another. Processes such as electron transport and generating ATP use proton pumps.[4] A G-protein coupled receptor is a single polypeptide chain that crosses the lipid bilayer seven times responding to signal molecules (i.e. hormones and neurotransmitters). G-protein coupled receptors are used in processes such as cell to cell signaling, the regulation of the production of cAMP, and the regulation of ion channels.[4]

The cell membrane, being exposed to the outside environment, is an important site of cell–cell communication. As such, a large variety of protein receptors and identification proteins, such as antigens, are present on the surface of the membrane. Functions of membrane proteins can also include cell–cell contact, surface recognition, cytoskeleton contact, signaling, enzymatic activity, or transporting substances across the membrane.

Most membrane proteins must be inserted in some way into the membrane.[28] For this to occur, an N-terminus "signal sequence" of amino acids directs proteins to the endoplasmic reticulum, which inserts the proteins into a lipid bilayer. Once inserted, the proteins are then transported to their final destination in vesicles, where the vesicle fuses with the target membrane.

Function

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A detailed diagram of the cell membrane
Illustration depicting cellular diffusion

The cell membrane surrounds the cytoplasm of living cells, physically separating the intracellular components from the extracellular environment. The cell membrane also plays a role in anchoring the cytoskeleton to provide shape to the cell, and in attaching to the extracellular matrix and other cells to hold them together to form tissues. Fungi, bacteria, most archaea, and plants also have a cell wall, which provides a mechanical support to the cell and precludes the passage of larger molecules.

The cell membrane is selectively permeable and able to regulate what enters and exits the cell, thus facilitating the transport of materials needed for survival. The movement of substances across the membrane can be achieved by either passive transport, occurring without the input of cellular energy, or by active transport, requiring the cell to expend energy in transporting it. The membrane also maintains the cell potential. The cell membrane thus works as a selective filter that allows only certain things to come inside or go outside the cell. The cell employs a number of transport mechanisms that involve biological membranes:

  1. Passive osmosis and diffusion: Some substances (small molecules, ions) such as carbon dioxide (CO2) and oxygen (O2), can move across the plasma membrane by diffusion, which is a passive transport process. Because the membrane acts as a barrier for certain molecules and ions, they can occur in different concentrations on the two sides of the membrane. Diffusion occurs when small molecules and ions move freely from high concentration to low concentration in order to equilibrate the membrane. It is considered a passive transport process because it does not require energy and is propelled by the concentration gradient created by each side of the membrane.[29] Such a concentration gradient across a semipermeable membrane sets up an osmotic flow for the water. Osmosis, in biological systems involves a solvent, moving through a semipermeable membrane similarly to passive diffusion as the solvent still moves with the concentration gradient and requires no energy. While water is the most common solvent in cell, it can also be other liquids as well as supercritical liquids and gases.[30]
  2. Transmembrane protein channels and transporters: Transmembrane proteins extend through the lipid bilayer of the membranes; they function on both sides of the membrane to transport molecules across it.[31] Nutrients, such as sugars or amino acids, must enter the cell, and certain products of metabolism must leave the cell. Such molecules can diffuse passively through protein channels such as aquaporins in facilitated diffusion or are pumped across the membrane by transmembrane transporters. Protein channel proteins, also called permeases, are usually quite specific, and they only recognize and transport a limited variety of chemical substances, often limited to a single substance. Another example of a transmembrane protein is a cell-surface receptor, which allow cell signaling molecules to communicate between cells.[31]
  3. Endocytosis: Endocytosis is the process in which cells absorb molecules by engulfing them. The plasma membrane creates a small deformation inward, called an invagination, in which the substance to be transported is captured. This invagination is caused by proteins on the outside on the cell membrane, acting as receptors and clustering into depressions that eventually promote accumulation of more proteins and lipids on the cytosolic side of the membrane.[32] The deformation then pinches off from the membrane on the inside of the cell, creating a vesicle containing the captured substance. Endocytosis is a pathway for internalizing solid particles ("cell eating" or phagocytosis), small molecules and ions ("cell drinking" or pinocytosis), and macromolecules. Endocytosis requires energy and is thus a form of active transport.
  4. Exocytosis: Just as material can be brought into the cell by invagination and formation of a vesicle, the membrane of a vesicle can be fused with the plasma membrane, extruding its contents to the surrounding medium. This is the process of exocytosis. Exocytosis occurs in various cells to remove undigested residues of substances brought in by endocytosis, to secrete substances such as hormones and enzymes, and to transport a substance completely across a cellular barrier. In the process of exocytosis, the undigested waste-containing food vacuole or the secretory vesicle budded from Golgi apparatus, is first moved by cytoskeleton from the interior of the cell to the surface. The vesicle membrane comes in contact with the plasma membrane. The lipid molecules of the two bilayers rearrange themselves and the two membranes are, thus, fused. A passage is formed in the fused membrane and the vesicles discharges its contents outside the cell.

Prokaryotes

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Prokaryotes are divided into two different groups: Archaea and Bacteria, with bacteria dividing further into gram-positive and gram-negative. Gram-negative bacteria have both a plasma membrane and an outer membrane separated by periplasm; however, other prokaryotes have only a plasma membrane. These two membranes differ in many aspects. The outer membrane of the gram-negative bacteria differs from other prokaryotes due to lipopolysaccharides forming the exterior of the bilayer, and lipoproteins and phospholipids forming the interior.[33] The outer membrane typically has a porous quality due to membrane proteins such as porins, which are pore-forming proteins. The inner plasma membrane is also generally symmetric, whereas the outer membrane is asymmetric because of proteins such as the aforementioned.[clarification needed]

Also, for the prokaryotic membranes, there are multiple things that can affect the fluidity. One of the major factors that can affect the fluidity is fatty acid composition. For example, when Staphylococcus aureus was grown at 37 °C for 24 h, the membrane exhibited a more fluid state instead of a gel-like state. This supports the concept that in higher temperatures, the membrane is more fluid than in colder temperatures. When the membrane is becoming more fluid and needs to become more stabilized, it will make longer fatty acid chains or saturated fatty acid chains in order to help stabilize the membrane.[34]

Bacteria are also surrounded by a cell wall composed of peptidoglycan (amino acids and sugars). Some eukaryotic cells also have cell walls, but none that are made of peptidoglycan. The outer membrane of gram negative bacteria is rich in lipopolysaccharides, which are combined poly- or oligosaccharide and saccharolipid that stimulate the cell's natural immunity.[35] The outer membrane can bleb out into periplasmic protrusions under stress conditions or upon virulence requirements while encountering a host target cell, and thus such blebs may work as virulence organelles.[36] Bacterial cells provide numerous examples of the diverse ways in which prokaryotic cell membranes are adapted with structures that suit the organism's niche. For example, proteins on the surface of certain bacterial cells aid in their gliding motion.[37] Many gram-negative bacteria have cell membranes which contain ATP-driven protein exporting systems.[37]

Structures

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Fluid mosaic model

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According to the fluid mosaic model of S. J. Singer and G. L. Nicolson (1972), which replaced the earlier model of Davson and Danielli, biological membranes can be considered as a two-dimensional liquid in which lipid and protein molecules diffuse more or less easily.[38] Although the lipid bilayers that form the basis of the membranes do indeed form two-dimensional liquids by themselves, the plasma membrane also contains a large quantity of proteins, which provide more structure. Examples of such structures are protein-protein complexes, pickets and fences formed by the actin-based cytoskeleton, and potentially lipid rafts.

Lipid bilayer

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Diagram of the arrangement of amphipathic lipid molecules to form a lipid bilayer. The yellow polar head groups separate the grey hydrophobic tails from the aqueous cytosolic and extracellular environments.

Lipid bilayers form through the process of self-assembly. The cell membrane consists primarily of a thin layer of amphipathic phospholipids that spontaneously arrange so that the hydrophobic "tail" regions are isolated from the surrounding water while the hydrophilic "head" regions interact with the intracellular (cytosolic) and extracellular faces of the resulting bilayer. This forms a continuous, spherical lipid bilayer. Hydrophobic interactions (also known as the hydrophobic effect) are the major driving forces in the formation of lipid bilayers. An increase in interactions between hydrophobic molecules (causing clustering of hydrophobic regions) allows water molecules to bond more freely with each other, increasing the entropy of the system. This complex interaction can include noncovalent interactions such as van der Waals, electrostatic and hydrogen bonds.

Lipid bilayers are generally impermeable to ions and polar molecules. The arrangement of hydrophilic heads and hydrophobic tails of the lipid bilayer prevent polar solutes (ex. amino acids, nucleic acids, carbohydrates, proteins, and ions) from diffusing across the membrane, but generally allows for the passive diffusion of hydrophobic molecules. This affords the cell the ability to control the movement of these substances via transmembrane protein complexes such as pores, channels and gates. Flippases and scramblases concentrate phosphatidyl serine, which carries a negative charge, on the inner membrane. Along with NANA, this creates an extra barrier to charged moieties moving through the membrane.

Membranes serve diverse functions in eukaryotic and prokaryotic cells. One important role is to regulate the movement of materials into and out of cells. The phospholipid bilayer structure (fluid mosaic model) with specific membrane proteins accounts for the selective permeability of the membrane and passive and active transport mechanisms. In addition, membranes in prokaryotes and in the mitochondria and chloroplasts of eukaryotes facilitate the synthesis of ATP through chemiosmosis.[8]

Membrane polarity

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See also: Epithelial polarity
Alpha intercalated cell

The apical membrane or luminal membrane of a polarized cell is the surface of the plasma membrane that faces inward to the lumen. This is particularly evident in epithelial and endothelial cells, but also describes other polarized cells, such as neurons. The basolateral membrane or basolateral cell membrane of a polarized cell is the surface of the plasma membrane that forms its basal and lateral surfaces.[39] It faces outwards, towards the interstitium, and away from the lumen. Basolateral membrane is a compound phrase referring to the terms "basal (base) membrane" and "lateral (side) membrane", which, especially in epithelial cells, are identical in composition and activity. Proteins (such as ion channels and pumps) are free to move from the basal to the lateral surface of the cell or vice versa in accordance with the fluid mosaic model. Tight junctions join epithelial cells near their apical surface to prevent the migration of proteins from the basolateral membrane to the apical membrane. The basal and lateral surfaces thus remain roughly equivalent[clarification needed] to one another, yet distinct from the apical surface.

Membrane structures

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Diagram of the cell membrane's structures

Cell membrane can form different types of "supramembrane" structures such as caveolae, postsynaptic density, podosomes, invadopodia, focal adhesion, and different types of cell junctions. These structures are usually responsible for cell adhesion, communication, endocytosis and exocytosis. They can be visualized by electron microscopy or fluorescence microscopy. They are composed of specific proteins, such as integrins and cadherins.

Cytoskeleton

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The cytoskeleton is found underlying the cell membrane in the cytoplasm and provides a scaffolding for membrane proteins to anchor to, as well as forming organelles that extend from the cell. Indeed, cytoskeletal elements interact extensively and intimately with the cell membrane.[40] Anchoring proteins restricts them to a particular cell surface — for example, the apical surface of epithelial cells that line the vertebrate gut — and limits how far they may diffuse within the bilayer. The cytoskeleton is able to form appendage-like organelles, such as cilia, which are microtubule-based extensions covered by the cell membrane, and filopodia, which are actin-based extensions. These extensions are ensheathed in membrane and project from the surface of the cell in order to sense the external environment and/or make contact with the substrate or other cells. The apical surfaces of epithelial cells are dense with actin-based finger-like projections known as microvilli, which increase cell surface area and thereby increase the absorption rate of nutrients. Localized decoupling of the cytoskeleton and cell membrane results in formation of a bleb.

Intracellular membranes

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The content of the cell, inside the cell membrane, is composed of numerous membrane-bound organelles, which contribute to the overall function of the cell. The origin, structure, and function of each organelle leads to a large variation in the cell composition due to the individual uniqueness associated with each organelle.

  • Mitochondria and chloroplasts are considered to have evolved from bacteria, known as the endosymbiotic theory. This theory arose from the idea that Paracoccus and Rhodopseudomonas, types of bacteria, share similar functions to mitochondria and blue-green algae (cyanobacteria) share similar functions to chloroplasts. Endosymbiotic theory proposes that through the course of evolution, a eukaryotic cell engulfed these two types of bacteria, leading to the formation of mitochondria and chloroplasts inside eukaryotic cells. This engulfment lead to the double-membranes systems of these organelles in which the outer membrane originated from the host's plasma membrane and the inner membrane was the endosymbiont's plasma membrane. Considering that mitochondria and chloroplasts both contain their own DNA is further support that both of these organelles evolved from engulfed bacteria that thrived inside a eukaryotic cell.[41]
  • In eukaryotic cells, the nuclear membrane separates the contents of the nucleus from the cytoplasm of the cell.[42] The nuclear membrane is formed by an inner and outer membrane, providing the strict regulation of materials in to and out of the nucleus. Materials move between the cytosol and the nucleus through nuclear pores in the nuclear membrane. If a cell's nucleus is more active in transcription, its membrane will have more pores. The protein composition of the nucleus can vary greatly from the cytosol as many proteins are unable to cross through pores via diffusion. Within the nuclear membrane, the inner and outer membranes vary in protein composition, and only the outer membrane is continuous with the endoplasmic reticulum (ER) membrane. Like the ER, the outer membrane also possesses ribosomes responsible for producing and transporting proteins into the space between the two membranes. The nuclear membrane disassembles during the early stages of mitosis and reassembles in later stages of mitosis.[43]
  • The ER, which is part of the endomembrane system, which makes up a very large portion of the cell's total membrane content. The ER is an enclosed network of tubules and sacs, and its main functions include protein synthesis, and lipid metabolism. There are 2 types of ER, smooth and rough. The rough ER has ribosomes attached to it used for protein synthesis, while the smooth ER is used more for the processing of toxins and calcium regulation in the cell.[44]
  • The Golgi apparatus has two interconnected round Golgi cisternae. Compartments of the apparatus forms multiple tubular-reticular networks responsible for organization, stack connection and cargo transport that display a continuous grape-like stringed vesicles ranging from 50 to 60 nm. The apparatus consists of three main compartments, a flat disc-shaped cisterna with tubular-reticular networks and vesicles.[45]

Variations

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The cell membrane has different lipid and protein compositions in distinct types of cells and may have therefore specific names for certain cell types.

  • Sarcolemma in muscle cells: Sarcolemma is the name given to the cell membrane of muscle cells.[46] Although the sarcolemma is similar to other cell membranes, it has other functions that set it apart. For instance, the sarcolemma transmits synaptic signals, helps generate action potentials, and is very involved in muscle contraction.[47] Unlike other cell membranes, the sarcolemma makes up small channels called T-tubules that pass through the entirety of muscle cells. It has also been found that the average sarcolemma is 10 nm thick as opposed to the 4 nm thickness of a general cell membrane.[48][46]
  • Oolemma is the cell membrane of an oocyte: The oolemma of an oocyte, (immature egg cell) is not consistent with a lipid bilayer as the bilayer is not present and does not consist of lipids.[49] Rather, the structure has an inner layer, the fertilization envelope, and the exterior is made up of the zona pellucida (vitelline membrane in non-mammals), which is made up of glycoproteins; however, channels and proteins are still present for their functions in the membrane.
  • Axolemma: The specialized plasma membrane on the axons of nerve cells that is responsible for the generation of the action potential. It consists of a granular, densely packed lipid bilayer that works closely with the cytoskeleton components spectrin and actin. These cytoskeleton components are able to bind to and interact with transmembrane proteins in the axolemma.[50][51]

Permeability

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See also: Intestinal permeability

The permeability of a membrane is the rate of passive diffusion of molecules through the membrane. These molecules are known as permeant molecules. Permeability depends mainly on the electric charge and polarity of the molecule and to a lesser extent the molar mass of the molecule. Due to the cell membrane's hydrophobic nature, small electrically neutral molecules pass through the membrane more easily than charged, large ones. The inability of charged molecules to pass through the cell membrane results in pH partition of substances throughout the fluid compartments of the body[citation needed].

See also

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Notes and references

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Cell membrane

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from Grokipedia
The cell membrane, also known as the plasma membrane, is a selectively permeable that encloses the contents of most cells, separating the intracellular environment from the and regulating the exchange of materials across this boundary. It consists of a double layer of phospholipids, which are amphipathic molecules with hydrophilic heads facing the aqueous environments on both sides and hydrophobic tails forming the inner core, providing a fundamental barrier to water-soluble substances. Embedded within this bilayer are proteins, , and carbohydrates, which together enable the membrane's dynamic structure and multifaceted roles in cellular function. The structure of the cell membrane is best described by the , proposed by Singer and Nicolson in 1972 and refined in subsequent research, which portrays it as a two-dimensional fluid where and proteins can diffuse laterally, creating a mosaic-like arrangement influenced by factors such as temperature, composition, and protein crowding. Proteins constitute about 50% of the membrane's mass in typical plasma membranes, including proteins that span the bilayer to form channels and transporters, and peripheral proteins that associate with the surface for enzymatic or structural support. molecules intercalate between phospholipids to modulate and thickness, preventing excessive rigidity at low temperatures and fluidity at high temperatures. In terms of function, the cell membrane serves as a protective barrier that maintains cell integrity while selectively controlling the influx and efflux of ions, nutrients, and waste products through passive , facilitated , and active pumping mechanisms mediated by membrane proteins. It also plays critical roles in , where receptor proteins bind extracellular ligands to trigger intracellular responses; , facilitating interactions with neighboring cells or the ; and processes like and for bulk . Additionally, the membrane's asymmetry— with distinct and protein distributions on its inner and outer leaflets—supports vectorial and ensures proper orientation for functions such as electron in organelles. These properties make the cell membrane essential for cellular , communication, and survival across prokaryotic and eukaryotic organisms.

Composition

Lipids

The cell membrane's foundational matrix is primarily composed of , which provide a hydrophobic barrier essential for cellular integrity and function. The main lipid classes include phospholipids, , glycolipids, and . Phospholipids form the bulk of the membrane's lipid component, while modulates its physical properties, and glycolipids and contribute to structural diversity and specific interactions. These lipids collectively account for approximately 40-50% of the mass in typical eukaryotic plasma membranes, with the remainder primarily consisting of proteins. Phospholipids are amphipathic molecules characterized by a hydrophilic head group and hydrophobic tails, enabling their into bilayers. The head group typically consists of a moiety attached to a backbone or , paired with two hydrophobic chains that form the tails. Common examples include , which predominates in the outer leaflet and features a choline head, and , more abundant in the inner leaflet with an head. The nature of the tails significantly influences membrane properties: saturated tails, lacking double bonds, pack tightly and promote rigidity, whereas unsaturated tails with cis double bonds introduce kinks, enhancing fluidity and reducing the gel-to-liquid crystalline temperature. Cholesterol, a , intercalates between molecules, embedding its rigid ring structure within the hydrophobic tails to regulate and thickness. At physiological concentrations (often 20-50 mol% in animal cell membranes), cholesterol restricts the motion of tails, preventing excessive fluidity at high temperatures by filling packing voids and increasing order, while counteracting rigidity at low temperatures by disrupting tight chain alignment. This modulation maintains optimal membrane thickness, typically around 4-5 nm, which is crucial for embedding membrane proteins and ensuring . Glycolipids and add further complexity to the lipid matrix. Glycolipids consist of a lipid anchor, such as , linked to chains, primarily residing in the outer leaflet to facilitate cell recognition and adhesion. , including , share a backbone with one and a polar head, contributing to membrane raft formation and signaling domains due to their tendency to cluster with . To study these lipids, researchers employ lipid vesicles, or liposomes, as model systems that mimic membrane behavior. Phospholipids spontaneously self-assemble in aqueous environments into closed bilayer structures, driven by the , where tails sequester away from water and heads face the aqueous phases. These unilamellar or multilamellar vesicles, formed via techniques like or , allow controlled investigation of lipid packing, permeability, and phase behavior without cellular complexity.

Proteins

Membrane proteins are broadly classified into two categories based on their association with the : integral membrane proteins, which are embedded within the bilayer, and peripheral membrane proteins, which are loosely attached to the membrane surface. Integral proteins span the hydrophobic core of the bilayer, often via transmembrane domains, and require harsh treatments like detergents for extraction, whereas peripheral proteins bind through noncovalent interactions or lipid anchors and can be dissociated with milder agents such as high salt or pH changes. Integral membrane proteins include diverse functional types such as channels, carriers, and receptors. Channels like aquaporins form pores that allow selective passage of water molecules across the membrane. Carriers, exemplified by (GLUT) proteins, facilitate the movement of solutes like glucose via conformational changes without forming open pores. Receptors, such as G-protein-coupled receptors (GPCRs), typically feature seven transmembrane alpha-helices and bind extracellular ligands to initiate intracellular signaling cascades. Peripheral membrane proteins, in contrast, do not penetrate the bilayer but associate with its exposed surfaces or integral proteins. A key example is spectrin, which acts as a cytoskeletal anchor in erythrocytes, forming a network that provides mechanical support to the red blood cell membrane. In eukaryotic plasma membranes, proteins constitute approximately 50% of the total mass by weight, varying by cell type—for instance, lower in myelin (~25%) and higher in mitochondrial inner membranes (~75%). Most transmembrane domains in these proteins consist of alpha-helices, typically 20-25 amino acids long, that span the ~30-40 Å thickness of the bilayer; single-pass proteins have one such helix, while multipass proteins like GPCRs or ion pumps feature bundles of 7-12 helices. Some bacterial outer membrane proteins use beta-barrels instead, but alpha-helical domains predominate in eukaryotic membranes. Many membrane proteins undergo post-translational modifications, including , where chains are attached to (N-linked) or serine/ (O-linked) residues, primarily on the extracellular or luminal side. This modification, affecting the majority of transmembrane proteins in cells, influences , stability, and cell-cell recognition; for example, the erythrocyte protein bears ~100 sugar residues comprising 60% of its mass. The density of membrane proteins varies but typically ranges from 10^4 to 10^5 molecules per square micrometer in the plasma membrane, leading to an estimated 10^6 to 10^8 proteins per eukaryotic cell depending on surface area. In human erythrocytes, for instance, major integral proteins like band 3 and number around 10^6 copies each, while peripheral spectrin is present at ~2.5 × 10^5 copies per cell.

Carbohydrates

Carbohydrates constitute approximately 5-10% of the mass of the plasma membrane and are exclusively located on the extracellular leaflet, contributing to membrane asymmetry. They are primarily attached to proteins or , forming glycoproteins and glycolipids, which together create the —a fuzzy, carbohydrate-rich coating that extends outward from the cell surface. This layer provides a hydrophilic barrier and plays key roles in cellular interactions with the environment. The structural diversity of membrane carbohydrates arises from oligosaccharides, which are short chains typically comprising 2-15 sugar units, in contrast to longer found in other cellular contexts. In glycoproteins, these attach via N-linked , where sugars bind to the nitrogen atom of residues in proteins, or O-linked , involving linkage to the oxygen of serine or . Glycolipids feature similar chains covalently bound to heads, such as ceramides, enhancing the membrane's surface complexity. These attachments occur during protein or synthesis in the and Golgi apparatus, ensuring the carbohydrates face outward upon membrane insertion. Membrane carbohydrates are crucial for cell recognition, serving as molecular tags that distinguish self from non-self. In the , specific antigens on surfaces determine blood types: A and B antigens involve terminal or additions to a core , while type O lacks these extensions. These markers are recognized by antibodies, influencing transfusion compatibility and immune responses. Additionally, carbohydrates mediate cell-cell adhesion through interactions with on opposing cells; for instance, selectins on endothelial cells bind sialylated oligosaccharides on leukocytes, facilitating rolling and temporary attachment during . Beyond recognition, contribute to cellular protection, particularly via mucins—highly glycosylated proteins abundant on epithelial cells. Mucins, such as MUC1, form a dense that acts as a , reducing friction between cells and their environment while preventing through steric hindrance and negative charge repulsion. In respiratory and gastrointestinal epithelia, this lubrication supports clearance and maintains tissue hydration, underscoring the protective role of these carbohydrate structures.

Molecular Structure

Lipid Bilayer

The forms the foundational architecture of the cell membrane through the spontaneous of phospholipids in aqueous environments, driven primarily by the , where nonpolar tails aggregate to minimize contact with water while polar head groups interact with the surrounding aqueous medium on both sides. This arrangement results in a symmetrical double layer, with hydrophilic heads oriented outward toward the extracellular and intracellular spaces and hydrophobic tails sequestered inward, forming a nonpolar core that acts as a barrier to polar solutes. The thickness of the lipid bilayer typically ranges from 5 to 10 nm, encompassing the polar head groups and the hydrophobic core, with variations influenced by the length and degree of saturation of the acyl chains; longer saturated chains increase thickness by promoting tighter packing, whereas unsaturated chains introduce that reduce overall bilayer density and thickness. Within the plane of the bilayer, lipids exhibit lateral , allowing them to move freely relative to one another, characterized by a diffusion coefficient on the order of 10^{-8} cm²/s in the liquid-crystalline phase, which contributes to the membrane's dynamic nature. Lipid bilayers undergo phase transitions between a state, where acyl chains are ordered and tightly packed at lower temperatures, and a liquid-crystalline state, featuring disordered chains and higher fluidity at physiological temperatures; the transition temperature (T_m) depends on composition, with saturated having higher T_m values due to straighter chains that facilitate gel-phase stability, while unsaturation and shorter chains lower T_m. Experimental evidence for the bilayer structure was provided by freeze-fracture electron microscopy, a technique that rapidly freezes samples and fractures them along planes of weakness, revealing a characteristic split within the hydrophobic core that exposes inner leaflet surfaces (P-face and E-face), confirming the existence of a central nonpolar region flanked by polar layers.

Fluid Mosaic Model

The Fluid Mosaic Model, proposed by S.J. Singer and G.L. Nicolson in 1972, conceptualizes the cell membrane as a dynamic, two-dimensional fluid where and proteins are free to diffuse laterally within the plane of the bilayer, forming a mosaic-like arrangement of components. In this model, the bilayer serves as a viscous in which integral proteins are embedded like icebergs floating in a of , while peripheral proteins associate loosely with the surface, allowing for flexible interactions and rearrangements essential to membrane function. The model emphasizes that this fluidity arises from the amphipathic nature of lipids, enabling weak hydrophobic interactions that permit rapid lateral movement without disrupting the overall structure. Key features of the model include the predominantly random distribution of proteins and , with diffusion rates enabling proteins to traverse the membrane surface in seconds to minutes, though mobility is not uniform due to interactions with the underlying . Restricted diffusion occurs through "cytoskeletal fences," where filaments and associated proteins form barriers that corral membrane components into compartments approximately 100-300 nm in diameter, requiring occasional "hopping" events for long-range movement. Evidence supporting lateral mobility came from (FRAP) experiments, which demonstrated that bleached fluorescent labels on membrane recover up to 80-100% of signal within seconds, indicating diffusion coefficients of about 1-10 μm²/s, while proteins show slower recovery (0.01-1 μm²/s) due to size and interactions. Subsequent updates to the model incorporate lipid rafts—transient, - and sphingolipid-enriched domains that act as platforms for protein sorting and signaling, modulating the original view of uniform fluidity. These rafts, first proposed as functional entities in , form ordered microdomains (10-200 nm) that can transiently associate and dissociate, enhancing compartmentalization without contradicting the core fluid mosaic principle. Despite its foundational role, the model has limitations, as membranes are not uniformly fluid; dense protein crowding and stable lipid domains in certain regions reduce overall mobility, and the presence of rafts acknowledges non-random that the original description did not fully anticipate. This refined understanding highlights that while lateral predominates, transverse constraints and dynamic barriers create a more partitioned fluidity.

Membrane Asymmetry

The cell membrane exhibits transverse , characterized by a non-uniform distribution of , , and carbohydrates between the inner (cytoplasmic) and outer (extracellular) leaflets of the . This organization is essential for membrane function and is actively maintained against the tendency for spontaneous equilibration. is a hallmark of eukaryotic plasma membranes, with the outer leaflet enriched in neutral phospholipids such as (PC) and (SM), which contribute to a more rigid and charged surface. In contrast, the inner leaflet is predominantly composed of aminophospholipids, including (PE) and (PS), which bear negative charges and interact with cytoplasmic components. This distribution is not random but arises from the biophysical properties of and energy-dependent translocation mechanisms. Protein asymmetry complements this lipid organization, as most transmembrane proteins adopt a specific orientation with functional domains directed either toward the or the . For instance, receptors and channels often position ligand-binding sites extracellularly, while enzymatic or signaling domains face the , ensuring directional functionality in processes like and signaling. This absolute in protein topology is enforced during biosynthesis and insertion into the , guided by sequence motifs such as the positive-inside rule, which favors cytoplasmic retention of positively charged residues. Carbohydrates in the membrane are exclusively localized to the extracellular leaflet, attached to proteins as glycoproteins or to as glycolipids, forming the that mediates cell-cell recognition and protection. This sidedness arises from the topology of machinery in the and Golgi, which adds sugars only to the luminal (future extracellular) side. The maintenance of membrane asymmetry relies on ATP-dependent lipid translocators. Flippases, primarily P4-ATPases such as ATP11A and ATP11C, actively transport PS and PE from the outer to the inner leaflet, countering passive flip-flop. Floppases, including ABC transporters like , move PC and SM outward to the extracellular leaflet. In contrast, scramblases, such as TMEM16F or Xkr8, facilitate bidirectional lipid movement and are activated under specific conditions like calcium influx or to disrupt asymmetry when needed. These enzymes consume energy to sustain the non-equilibrium state, with flippases and floppases working in concert to generate and preserve the gradient. Biologically, membrane plays critical roles in cellular ; for example, the exposure of PS on the outer leaflet during , triggered by caspase-mediated inactivation of flippases and activation of scramblases like Xkr8, serves as an "eat-me" signal recognized by via receptors such as TIM-4 and TAM, promoting efficient clearance without . Loss of this asymmetry can lead to pathological conditions, including if apoptotic cells accumulate.

Functions

Selective Permeability

The cell membrane exhibits selective permeability, allowing certain molecules to pass through passively while restricting others, primarily due to the hydrophobic nature of the . Small, nonpolar molecules such as oxygen (O₂) and (CO₂) diffuse freely across the membrane down their concentration gradients, as they can readily dissolve in the lipid environment without requiring energy or protein assistance. In contrast, polar or charged molecules, including ions like sodium (Na⁺) and (K⁺), as well as larger polar solutes like glucose, face significant barriers and exhibit very low passive rates, often orders of magnitude slower than nonpolar gases. This selectivity ensures that the membrane acts as a protective barrier, preventing the uncontrolled loss of essential cellular contents and maintaining critical electrochemical gradients, such as the high intracellular and low sodium concentrations vital for cellular functions like impulse transmission. The rate of passive diffusion is governed by several key factors: the molecule's lipid solubility, molecular size, and charge. Lipid solubility, often quantified by the (K_{ow}), correlates strongly with permeability, as higher facilitates partitioning into the hydrophobic core of the bilayer; for instance, experimental measurements using octanol-water systems model this behavior to predict membrane crossing efficiency. Smaller molecules permeate more easily than larger ones due to reduced steric hindrance, while charged are repelled by the nonpolar interior, rendering their passive permeability negligible. Permeability coefficients (P), expressed in cm/s, illustrate these differences in artificial lipid bilayers approximating cell membranes: O₂ has a high P of approximately 23 cm/s, CO₂ around 0.35 cm/s, and water a modest passive P of about 3.4 × 10^{-3} cm/s, though water's effective permeability can increase via specialized channels like aquaporins. For comparison, ions like Na⁺ show extremely low P values on the order of 5 × 10^{-14} cm/s, and glucose's passive P is similarly minimal, necessitating assisted transport mechanisms for physiological rates. An exception to typical restrictions occurs with highly lipophilic substances, such as volatile anesthetic gases (e.g., ), which cross membranes rapidly due to their favorable partitioning into , enabling quick into cells despite their size. Overall, this passive barrier property underpins the membrane's role in , with facilitated or providing pathways for impermeable solutes as detailed in subsequent discussions.

Transport Mechanisms

The cell membrane's is largely impermeable to polar solutes and ions, necessitating specialized protein-mediated transport mechanisms to facilitate the movement of essential molecules across it. These mechanisms include , which relies on concentration or electrochemical gradients without direct input; , which uses cellular to move substances against gradients; and vesicular transport, which involves membrane-bound vesicles for bulk movement. Together, these processes maintain cellular , nutrient uptake, and waste removal. Passive transport occurs via facilitated diffusion through membrane proteins such as channels and carriers. Ion channels, like potassium leak channels, form selective pores that allow ions to diffuse down their electrochemical gradients, contributing significantly to the resting . For instance, K⁺ leak channels permit passive efflux of potassium ions, balancing the higher intracellular K⁺ concentration. Carrier proteins, such as the glucose transporter GLUT1, undergo conformational changes to shuttle substrates across the membrane without energy expenditure, enabling bidirectional transport until equilibrium is reached. The kinetics of carrier-mediated transport follow Michaelis-Menten equation, where the transport rate vv is given by v=Vmax⁡[S]Km+[S],v = \frac{V_{\max} [S]}{K_m + [S]}, with Vmax⁡V_{\max} as the maximum transport rate, [S] as substrate concentration, and KmK_m as the concentration at half Vmax⁡V_{\max}, reflecting saturation at high substrate levels. Active transport counters concentration gradients using energy derived from ATP hydrolysis or ion gradients. Primary active transport directly couples ATP hydrolysis to solute movement, exemplified by the Na⁺/K⁺-ATPase pump, which exports three Na⁺ ions and imports two K⁺ ions per ATP molecule hydrolyzed, establishing essential electrochemical gradients across the plasma membrane. This pump, discovered by Jens Christian Skou in 1957, is a P-type ATPase with a catalytic cycle involving phosphorylation and dephosphorylation for ion translocation. Secondary active transport harnesses the Na⁺ gradient created by the Na⁺/K⁺-ATPase to drive cotransport of other solutes; the sodium-glucose linked transporter (SGLT) exemplifies this by symporting one glucose molecule with two Na⁺ ions into cells, such as in intestinal epithelia, against the glucose gradient. The equilibrium potential for ions in these systems is described by the Nernst equation: E=RTzFln⁡([out][in]),E = \frac{RT}{zF} \ln \left( \frac{[out]}{[in]} \right), where RR is the gas constant, TT is temperature, zz is ion valence, FF is Faraday's constant, and [out]/[in] are extracellular and intracellular concentrations, respectively, defining the membrane potential at which net ion flux ceases. Vesicular transport enables the bulk translocation of macromolecules and particles via membrane vesicles budding from or fusing with the plasma membrane. Endocytosis internalizes extracellular material: phagocytosis engulfs large particles like bacteria into phagosomes, primarily in immune cells, while pinocytosis non-selectively takes up fluids and solutes into small vesicles for nutrient acquisition. Exocytosis releases intracellular contents, such as hormones or neurotransmitters, by vesicle fusion with the membrane, often regulated by Ca²⁺ signals. These processes maintain membrane composition by recycling lipids and proteins. Active transport mechanisms collectively consume approximately 30% of a cell's ATP.

Cell Signaling and Adhesion

The cell membrane serves as a dynamic platform for intercellular signaling and adhesion, enabling cells to communicate chemical cues and maintain structural integrity within tissues. Embedded receptors and adhesion proteins detect extracellular ligands and facilitate interactions, translating environmental signals into intracellular responses that regulate processes such as development, immunity, and homeostasis. These functions rely on the precise organization of membrane components, which ensure specificity and efficiency in signal propagation and cell attachment. Receptors in the plasma membrane are pivotal for initiating signaling pathways. Ionotropic receptors function as , directly permitting ion flux upon ligand binding to elicit rapid postsynaptic effects, as exemplified by the , the founding member of the pentameric superfamily discovered in the electric organs of Torpedo fish. In contrast, metabotropic receptors, such as G protein-coupled receptors (GPCRs), operate through indirect mechanisms: ligand binding activates heterotrimeric G proteins, which in turn stimulate or inhibit effectors to produce second messengers like cyclic AMP (cAMP), enabling amplified and prolonged signaling; this paradigm was elucidated through pioneering work on beta-adrenergic receptors. Adhesion molecules anchored in the mediate physical connections essential for multicellular . Cadherins form homophilic, calcium-dependent bonds between adjacent cells, promoting tissue cohesion and ; their discovery as Ca²⁺-sensitive glycoproteins stemmed from studies dissociating and reassociating embryonic cells. , heterodimeric transmembrane proteins, bridge cells to the by binding ligands like , thereby integrating cytoskeletal dynamics with environmental cues; this family was identified through progressive biochemical fractionation of cell surface adhesion sites. Signal transduction pathways amplify membrane-initiated signals via enzymatic cascades. Receptor tyrosine kinases (RTKs), a major class of signaling receptors, undergo ligand-induced dimerization followed by trans-autophosphorylation of tyrosine residues, recruiting downstream effectors; in the , this process activates cascades that regulate and . The , a carbohydrate-rich layer on the membrane surface, aids in molecular recognition during immune responses. , such as galectins, bind specific glycan motifs within the glycocalyx to modulate leukocyte activation and pathogen discrimination, fine-tuning innate and adaptive immunity. Notable examples illustrate these roles in specialized contexts. The (TCR), a membrane-bound heterodimer, recognizes antigenic peptides presented by molecules, orchestrating adaptive immune responses; its discovery in the 1980s revolutionized understanding of T-cell specificity. Gap junctions, composed of proteins, form intercellular channels that enable direct cytoplasmic exchange of ions and small metabolites between coupled cells, supporting coordinated activities like electrical synchrony in cardiac tissue.

Variations

Prokaryotic Membranes

Prokaryotic cell membranes, found in and , differ fundamentally from eukaryotic membranes by lacking and other sterols, which are instead replaced by specialized that provide structural stability. In , hopanoids serve as functional analogs to sterols, embedding in the to enhance membrane order and rigidity, particularly in the outer membrane of Gram-negative species. , in contrast, feature ether-linked with isoprenoid chains connected via bonds to , conferring greater chemical stability compared to the ester-linked phospholipids typical in and eukaryotes. These enable to thrive in extreme environments, such as high temperatures or acidity. The structure of prokaryotic membranes is relatively simple, consisting of a single plasma membrane that envelops the without internal compartmentalization. This bilayer is primarily composed of phospholipids in , lacking the reinforcements seen in eukaryotic plasma membranes, which results in a more fluid but less rigid architecture under standard conditions. Invaginations known as mesosomes, appearing as vesicular or tubular extensions of the plasma membrane into the , have been observed in some prokaryotes, but their existence and function—potentially in , respiration, or —remain debated, with evidence suggesting they may be artifacts of fixation techniques used in electron microscopy. In terms of function, the prokaryotic plasma membrane serves as the primary site for , housing the (ETC) that generates a proton motive force for ATP synthesis via . In , the inner plasma membrane lies directly adjacent to the thick layer, facilitating interactions that support cell wall synthesis and maintenance. This association contrasts with the more separated periplasmic space in . A key variation occurs in Gram-negative bacteria, which possess an additional outer membrane beyond the plasma membrane, forming an asymmetric structure with lipopolysaccharides (LPS) dominating the outer leaflet. LPS, composed of lipid A, core polysaccharide, and O-antigen, provides a permeability barrier against antibiotics and host defenses, while integral β-barrel proteins called porins form water-filled channels that allow selective diffusion of small hydrophilic molecules like nutrients. This outer membrane endows Gram-negative prokaryotes with enhanced protection compared to the single-membrane setup in Gram-positive bacteria and archaea. Prokaryotic membranes exhibit remarkable adaptations, particularly in archaeal thermophiles, where branched isoprenoid chains in ether increase membrane packing and , preventing leakage at high temperatures above 80°C. These branched structures, often forming monolayer tetraether spanning the entire width, enhance stability and are crucial for survival in geothermal environments.

Eukaryotic Plasma Membranes

Eukaryotic plasma membranes, the outermost boundaries of animal, , and fungal cells, exhibit specialized compositions and structures adapted to their respective environments and functions. These membranes maintain cellular integrity while facilitating interactions with extracellular matrices, such as the in and fungi, and enabling intercellular communication. Unlike prokaryotic membranes, which lack sterols and are simpler in organization, eukaryotic plasma membranes incorporate diverse sterols that modulate fluidity and form dynamic domains critical for signaling and transport. In animal cells, cholesterol constitutes 30-50% of the plasma membrane , enhancing membrane rigidity and phase separation into ordered domains. Caveolae, flask-shaped invaginations rich in and , serve as platforms for , , and mechanosensing in non-muscle cells. A notable example is the erythrocyte plasma membrane, where the spectrin-based anchors to integral proteins like band 3 and , providing mechanical stability and deformability essential for circulation. Plant plasma membranes feature sterols such as β-sitosterol as the predominant component, comprising up to 60-80% of total sterols, which regulate membrane order and stress responses. These membranes closely associate with the rigid , composed of and , influencing maintenance. Plasmodesmata, specialized channels traversing the and lined by the plasma , enable symplastic transport of nutrients, hormones, and signaling molecules between cells, with their size exclusion limits dynamically regulated by callose deposition. Fungal plasma membranes are enriched in , the primary that modulates , permeability, and resistance to environmental stresses. integrates with the overlying , where microfibrils form covalent linkages to β-glucans via Crh proteins, anchoring the wall to the membrane and supporting hyphal growth and . Membrane asymmetry in eukaryotes, with and preferentially in the outer leaflet, contributes to the formation of lipid rafts—detergent-resistant domains that concentrate signaling proteins and facilitate entry, such as by viruses exploiting rafts for receptor clustering and internalization. Disruptions in these domains, including mutations in membrane proteins, underlie diseases; for instance, over 2,000 mutations in the CFTR gene cause by impairing protein trafficking to the plasma membrane, leading to defective ion transport and mucus accumulation in epithelial cells.

Intracellular Membranes

Intracellular membranes in eukaryotic cells form specialized compartments within organelles, enabling distinct biochemical environments and functions separate from the plasma membrane. These membranes, primarily bilayers, vary in composition and to support processes like protein modification, production, and degradation. Unlike the plasma membrane, which primarily serves as a barrier, intracellular membranes facilitate compartmentalization for efficient cellular . The (ER) consists of a network of interconnected tubules and flattened sacs continuous with the . The rough ER features ribosomes studded on its cytoplasmic surface, where these ribosomes synthesize proteins destined for or membrane insertion through co-translational translocation. In contrast, the smooth ER lacks ribosomes and specializes in synthesis, including phospholipids and steroids, as well as detoxification processes in certain cell types. This continuity with the allows the ER to exchange and proteins bidirectionally, maintaining nuclear integrity and supporting biogenesis across the cell. The Golgi apparatus comprises a stack of cisternae organized into cis, medial, and trans compartments, with gradients decreasing from approximately 6.7 in the cis-Golgi to 6.0 in the trans-Golgi, driven by vacuolar H+-ATPases. These gradients optimize reactions, where enzymes add moieties to proteins and for maturation. The stacked structure facilitates sorting of modified molecules into vesicles for transport to lysosomes, plasma membrane, or , ensuring precise trafficking. Mitochondria possess a double-membrane structure: an outer permeable to small molecules and an inner folded into cristae that house the and . Electron transport along the cristae generates a proton gradient, powering ATP synthesis via . This compartmentalization maximizes surface area for energy production, with cristae dynamics regulated by proteins like OPA1 to adapt to metabolic demands. Chloroplasts in photosynthetic eukaryotes similarly feature a double envelope and an internal membrane system, where stacked grana and stromal lamellae support light-driven electron transport, creating a proton gradient across thylakoids for ATP synthesis coupled to NADPH production. Lysosomes are single-membrane-bound vesicles with an acidic interior maintained at approximately 5 by V-type H+-ATPases in the membrane, which pump protons using . This low activates over 50 hydrolytic enzymes, including proteases, nucleases, and lipases, for degrading engulfed macromolecules, organelles, or pathogens via and . The membrane's proton pumps and protective prevent self-digestion while allowing selective transport of breakdown products to the . Lipid compositions of intracellular membranes differ to suit organelle-specific functions; for instance, the ER is enriched in , comprising a major portion of its phospholipids to support its role in and . In contrast, mitochondrial inner membranes contain high levels of , up to 20% of total , which stabilizes respiratory complexes and promotes cristae essential for efficient transport.

Historical Development

Early Discoveries

The initial recognition of cellular boundaries emerged in the through advancements in . In 1665, published Micrographia, describing the microscopic examination of cork slices, where he observed box-like compartments resembling the cells of a and coined the term "cells" for these structures, though he was viewing lignified cell walls rather than true membranes. Concurrently, Marcello Malpighi in 1675 detailed the microscopic anatomy of tissues in Anatome Plantarum, noting vesicular structures in plants and capillaries in animals, providing early evidence of compartmentalized cellular organization. , in his 1682 work The Anatomy of Plants, further described cell boundaries as delicate, lace-like membranes enclosing fluid-filled spaces. The 19th century brought a deeper understanding of cellular boundaries via physiological studies. In 1824, René Joachim Henri Dutrochet published Recherches anatomiques et physiologiques sur la structure intime des animaux et des végétaux, where he identified as the movement of water across semipermeable barriers in cells and animal tissues, attributing it to an invisible "living membrane" that selectively allowed solvent passage while retaining solutes. Building on this, in 1838 proposed that are aggregates of nucleated cells, and in 1839 extended this to animals in Mikroskopische Untersuchungen über die Übereinstimmung in der Struktur und dem Wachstum der Tiere und Pflanzen, formalizing and implying that cells are enclosed by bounding layers essential for their integrity. Wilhelm Pfeffer's 1877 experiments, detailed in his 1900 Osmotische Untersuchungen, quantified osmotic pressures in cells using artificial semipermeable membranes, reinforcing the concept of a dynamic, selective plasma membrane. Key insights into membrane composition arose from permeability research in the late 19th century. Charles Ernest Overton, through experiments from 1895 to 1899 published in the Vierteljahrsschrift der Naturforschenden Gesellschaft in Zürich, demonstrated that non-polar solutes like alcohols and anesthetics penetrate cells more readily than polar ones, correlating permeability with lipid solubility and proposing that cell boundaries consist of a lipoid layer capable of dissolving fats. Early structural models emerged in the 1920s and 1930s. In 1925, Evert Gorter and François Grendel extracted lipids from washed human erythrocytes, spread them into monolayers on water, and calculated that the total lipid area was approximately twice the cell surface area, leading them to propose a bimolecular lipid leaflet as the core of the red blood cell membrane. This bilayer hypothesis was refined in 1935 by James F. Danielli and Hugh Davson, who suggested a "sandwich" model in which a lipid bilayer is coated on both sides by protein layers, accounting for observed permeability and surface properties.

Modern Models and Advances

In 1972, S.J. Singer and G.L. Nicolson proposed the , which described the cell membrane as a dynamic bilayer of phospholipids with embedded proteins that could diffuse laterally, revolutionizing the understanding of membrane organization and gaining widespread acceptance as the foundational framework for subsequent research. This model emphasized the membrane's fluidity and heterogeneity, integrating prior observations of lipid bilayers while accounting for protein mobility observed through techniques like freeze-fracture electron microscopy. During the 1980s and , the discovery of lipid rafts—cholesterol- and sphingolipid-enriched domains—challenged aspects of uniform fluidity by revealing specialized microdomains resistant to extraction, first demonstrated in seminal work isolating these structures from epithelial cells. Fluorescence microscopy further advanced this insight in the late and early , enabling visualization of raft-like domains in model membranes and live cells, showing their role in protein sorting and signaling. In the 2000s, research on introduced the concept of nanodomains, highlighting how proteins with BAR (Bin/Amphiphysin/Rvs) domains actively shape bilayers through their banana-like structures, which sense and induce curvature to facilitate processes like . These domains, often forming scaffolds, underscored the membrane's active remodeling, integrating with nanodomains to create transient platforms for cellular functions. Recent advances from 2023 to 2025 have leveraged cryo-electron microscopy (cryo-EM) to resolve atomic-level protein-lipid interactions, such as those in membrane pores binding over 100 , revealing how specific stabilize protein conformations and influence transport. techniques have simultaneously provided dynamic views of lipid rafts, mapping their nanoscale organization in live cells and confirming their involvement in signaling pathways. Complementary studies on dynamic phase separations have shown how and protein mixtures undergo liquid-liquid phase transitions to form condensates at the membrane, driving processes such as bacterial division and polarity establishment. Additionally, AI-driven modeling has accelerated design, with tools like MEMPLEX enabling rapid prediction and synthesis of stable protein variants in artificial environments. Critiques of the original fluid mosaic model's emphasis on unrestricted fluidity have led to refinements, notably the "picket-fence" model proposed by A. Kusumi and colleagues, which posits that cytoskeletal fences and transmembrane "pickets" create compartments restricting protein to short-range hops, explaining observed mobility barriers. This shift highlights the membrane's compartmentalized nature, influenced by and dynamics, as evidenced in high-resolution tracking studies.

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