Plasma membranes (and all other organellar membranes for that matter) are more than just static lipid sheaths. Rather, they are fluid bilayers of amphipathic phospholipids— hydrophilic head groups that face the aqueous environment and hydrophobic lipid tails that interact with each other to form a barrier to passive diffusion of large or charged molecules (Fig. 1). The bilayer has a remarkably heterogeneous composition of different phospholipids that vary by location and are also asymmetric—that is, membrane lipids preferentially associate with extracellular or cytosolic faces. Proper localization of these molecules is important for cell health. For example, specific phospholipids interact with particular membrane proteins and modify their distributions and functions.

• Phosphatidylinositol on the inner membrane leaflet can be phosphorylated, serving as an electrostatic scaffold for intracellular proteins; alternatively, polyphosphoinositides can be hydrolyzed by phospholipase C to generate intracellular second signals like diacylglycerol and inositol trisphosphate.

• Phosphatidylserine is normally restricted to the inner face where it confers a negative charge involved in electrostatic protein interactions; however, when flipped to the extracellular leaflet, it becomes a potent “eat me” signal during programmed cell death (e.g., apoptosis). In platelets, phosphatidylserine is also a cofactor in blood clotting.

• Glycolipids and sphingomyelin are preferentially located on the extracellular face; glycolipids, including gangliosides with complex sugar linkages and terminal sialic acids that confer negative charges, support charge-based interactions that contribute to including inflammatory cell recruitment and sperm-egg fusion.

Fig1. Plasma membrane organization and asymmetry. (A) The plasma membrane is a bilayer of phospholipids, cholesterol, and associated proteins. The phospholipid distribution within the membrane is asymmetric due to the activity of flippases; phosphatidylcholine and sphingomyelin are overrepresented in the outer leaflet, and phosphatidylserine (negative charge) and phosphatidylethanolamine are predominantly found on the inner leaflet; glycolipids occur only on the outer face where they contribute to the extracellular glycocalyx. Although the membrane is laterally fluid and the various constituents can diffuse randomly, specific domains, for example cholesterol and glycosphingolipid-rich lipid rafts, can also form. (B) Membrane-associated proteins may traverse the membrane (singly or multiply) via α-helical hydrophobic amino acid sequences; depending on the membrane lipid content and relative hydrophobicity of protein domains, such proteins may have nonrandom distributions within the membrane. Proteins on the cytosolic face can be associated with the plasma membrane through posttranslational modifications (e.g., farnesylation) or addition of palmitic acid. Proteins on the extracytoplasmic face can associate with the membrane via glycosylphosphatidylinositol (GPI) linkages. Besides protein-protein interactions within the membrane, membrane proteins can also associate with extracellular and/or intracytoplasmic proteins to generate distinct domains (e.g., the focal adhesion complex). Transmembrane proteins can translate mechanical forces (e.g., from the cytoskeleton or extracellular matrix), as well as chemical signals across the membrane.

Despite substantial lateral fluidity, some membrane constituents concentrate into specialized domains (e.g., lipid rafts) that are enriched in glycosphingolipids and cholesterol. Since inserted membrane proteins have different intrinsic solubilities in domains with distinct lipid compositions, this membrane organization also impacts protein distribution. This geographic organization of plasma membrane components impacts cell-cell and cell-matrix interactions, intracellular signaling, and the specialized sites of vesicle budding or fusion.

The plasma membrane is liberally studded with a variety of proteins and glycoproteins involved in (1) ion and metabolite transport; (2) fluid-phase and receptor mediated uptake of macromolecules; and (3) cell-ligand, cell-matrix, and cell-cell interactions. The means by which these proteins associate with membranes frequently reflects function. For example, multiple transmembrane-spanning proteins are often pores or molecular transporters, while proteins that are superficially attached to the membrane via labile linkages are more likely to participate in signaling. In general, proteins associate with the lipid bilayer by one of four mechanisms.

• Most proteins are integral or transmembrane proteins, having one or more relatively hydrophobic α-helical segments that traverse the lipid bilayer.

• Proteins synthesized on free ribosomes in the cytosol may be modified posttranslationally by addition of prenyl groups (e.g., farnesyl, related to cholesterol) or fatty acids (e.g., palmitic or myristic acid) that insert into the cytosolic side of the plasma membrane.

• Proteins on the extracellular face of the membrane may be anchored by glycosylphosphatidylinositol (GPI) tails that are added posttranslationally.

• Peripheral membrane proteins may noncovalently associate with true transmembrane proteins.

Many plasma membrane proteins function as large complexes; these may be aggregated either under the control of chaperone molecules in the RER or by lateral diffusion in the plasma membrane, followed by complex formation in situ. For example, many protein receptors (e.g., cytokine receptors) dimerize or trimerize in the presence of ligand to form functional signaling units. Although lipid bilayers are fluid within the plane of the membrane, components can be confined to discrete domains. This can occur by localization to lipid rafts (discussed earlier) or through intercellular protein-protein interactions (e.g., tight junctions) that establish discrete boundaries and also have unique lipid composition. The latter strategy is used to maintain cell polarity (e.g., top/apical/free vs. bottom/basolateral/ bound to extracellular matrix [ECM]) in epithelial cells. Interactions of other membrane and cytosolic proteins with one another and the cytoskeleton also contributes to cell polarity.

The extracellular face of the plasma membrane is diffusely decorated by carbohydrates, not only as complex oligosaccharides on glycoproteins and glycolipids, but also as polysaccharide chains attached to integral membrane proteoglycans. This glycocalyx can form a chemical and mechanical barrier.

Membrane Transport

 Although the barrier provided by plasma membranes is critical, transport of selected molecules across the lipid bilayer or to intracellular sites via vesicular transport is essential. Several mechanisms contribute to this transport.

Passive Diffusion. Small, nonpolar molecules like O₂ and CO₂ readily dissolve in lipid bilayers and therefore rapidly diffuse across them. Larger hydrophobic molecules, (e.g., steroid-based molecules like estradiol or vitamin D) can also cross lipid bilayers with relative impunity. While small polar molecules such as water (18 Da) can also diffuse across membranes at low rates, in tissues responsible for significant water movement (e.g., renal tubular epithelium), special integral membrane proteins called aquaporins form transmembrane channels for water, H₂O₂, and other small molecules. In contrast, the lipid bilayer is an effective barrier to the passage of larger polar molecules (>75 Da); at 180 Da, for example, glucose is effectively excluded. Lipid bilayers are also impermeant to ions due to their charge and hydration.

Carriers and Channels (Fig. 2). Plasma membrane transport proteins are required for uptake and secretion of ions and larger molecules that are required for cellular function (e.g., nutrient uptake and waste disposal). Ions and small molecules can be transported by channel proteins and carrier proteins. Similar pores and channels also mediate transport across organellar membranes. These transporters that move ions, sugars, nucleotides, etc., frequently have exquisite specificities, and can be either active or passive (see below). For example, some transporters accommodate glucose but reject galactose.

 • Channel proteins create hydrophilic pores, which, when open, permit rapid movement of solutes (usually restricted by size and charge).

• Carrier proteins bind their specific solute and undergo a series of conformational changes to transfer the ligand across the membrane; their transport is relatively slow.

Fig2. Movement of small molecules and larger structures across membranes. The lipid bilayer is relatively impermeable to all but the smallest and/or most hydrophobic molecules. Thus the import or export of charged species requires specific transmembrane transporter proteins, vesicular traffic, or membrane deformations.

From left to right in the figure: Small charged solutes can move across the membrane using either channels or carriers; in general, each molecule requires a unique transporter. Channels are used when concentration gradients can drive the solute movement; activation of the channel opens a hydrophilic pore that allows size-restricted and charge-restricted flow. Carriers are required when solute is moved against a concentration gradient; this typically requires energy expenditure to drive a conformational change in the carrier that facilitates the transmembrane delivery of specific molecules.

 Receptor-mediated and fluid-phase uptake of material involves membrane bound vesicles. Caveolae endocytose extracellular fluid, membrane proteins, and some receptor bound molecules (e.g., folate) in a process driven by caveolin proteins concentrated within lipid rafts. They can subsequently fuse with endosomes or recycle to the membrane. Endocytosis of receptor-ligand pairs often involves clathrin-coated pits and vesicles. After internalization the clathrin disassembles and individual components can be re-used. The resulting vesicle becomes part of the endocytic pathway, in which compartments are progressively more acidic. After ligand is released, the receptor can be recycled to the plasma membrane to repeat the process (e.g., iron dissociates from transferin at pH ~5.5; apotransferrin and the transferrin receptor then return to the surface). Alternatively, receptor and ligand complexes can eventually be degraded within lysosomes (e.g., epidermal growth factor and its receptor are both degraded, which prevents excessive signaling). Exocytosis is the process by which membrane-bound vesicles fuse with the plasma membrane and discharge their contents to the extracellular space. This includes endosome recycling (shown), release of undigested residual material from lysosomes, transcytotic delivery of vesicles, and export of secretory vacuole contents (not shown). Phagocytosis involves membrane invagination to engulf large particles and is most common in specialized phagocytes (e.g., macrophages and neutrophils). The resulting phagosomes eventually fuse with lysosomes to facilitate the degradation of the internalized material. Transcytosis can mediate transcellular transport in either apical-to-basal or basal-to-apical directions, depending on the receptor and ligand.

Solute transport across the plasma membrane is frequently driven by a concentration and/or electrical gradient between the inside and outside of the cell via passive transport (virtually all plasma membranes have an electrical potential difference across them, with the inside negative relative to the outside). In other cases, active transport of certain solutes (against a concentration gradient) is accomplished by carrier molecules (never channels) at the expense of ATP hydrolysis or a coupled ion gradient. For example, most apical nutrient transporters in the intestines and renal tubules exploit the extracellular to intracellular Na⁺ gradient to allow absorption even when intracellular nutrient concentrations exceed extracellular concentrations. This form of active transport does not use ATP directly, but depends on the Na+ gradient generated by Na⁺-Ka⁺ ATPase. Other transporters are ATPases. One example is the multidrug resistance (MDR) protein, which pumps polar compounds (e.g., chemotherapeutic drugs) out of cells and may render cancer cells resistant to treatment.

Water movement into or out of cells is passive and directed by solute concentrations. Thus extracellular salt in excess of that in the cytoplasm (hypertonicity) causes net movement of water out of cells, while hypotonicity causes net movement of water into cells. Conversely, the charged metabolites and proteins within the cytoplasm attract charged counterions that increase intracellular osmolarity. Thus to prevent overhydration, cells must constantly pump out small inorganic ions (e.g., Na⁺)—typically through the activity of the membrane ion-exchanging ATPase. Loss of the ability to generate energy (e.g., in a cell injured by toxins or ischemia) therefore results in osmotic swelling and eventual cell rupture. Similar transport mechanisms also regulate concentrations of other ions (e.g., Ca²⁺ and H⁺). This is critical to many processes. For example, cytosolic enzymes are most active at pH 7.4 and are often regulated by Ca²⁺, whereas lysosomal enzymes function best at pH 5 or less.

Uptake of fluids or macromolecules by the cell is called endocytosis. Depending on the size of the vesicle, endocytosis may be denoted pinocytosis (“cellular drinking”) or phagocytosis (“cellular eating”). Generally, phagocytosis is restricted to certain cell types (e.g., macrophages and neutrophils) whose role is to specifically ingest invading organisms or dead cell fragments.

Receptor-Mediated and Fluid-Phase Uptake (see Fig. 2)

Certain small molecules—including some vitamins—bind to cell-surface receptors and are taken up through invaginations of the plasma membrane called caveolae. Uptake can also occur through membrane invaginations coated by an intracellular matrix of clathrin proteins that spontaneously assemble into a basket-like lattice which helps drive endocytosis (discussed more later). In both cases, activity of the “pinchase” dynamin is required for vesicle release.

Macromolecules can also be exported from cells by exocytosis. In this process, proteins synthesized and packaged within the RER and Golgi apparatus are concentrated in secretory vesicles, which then fuse with the plasma mem brane to expel their contents. Common examples include peptide hormones (e.g., insulin) and cytokines.

Transcytosis is the movement of endocytosed vesicles between the apical and basolateral compartments of cells. This is a mechanism for transferring large amounts of intact proteins across epithelial barriers (e.g., ingested antibodies in maternal milk) or for rapid movement of large solute volumes.

We now return to the specifics of endocytosis (see Fig. 2).

 • Caveolae-mediated endocytosis. Caveolae (“little caves”) are noncoated plasma membrane invaginations associated with GPI-linked molecules, cyclic adenosine monophosphate (cAMP) binding proteins, src-family kinases, and the folate receptor; caveolin is the major structural protein of caveolae, which, like membrane rafts (see above), are enriched in glycosphingolipids and cholesterol. Internalization of caveolae along with bound molecules and associated extracellular fluid is called potocytosis—literally “cellular sipping.” In addition to supporting transmem brane delivery of some molecules (e.g., folate), caveolae regulate transmembrane signaling and cellular adhesion via internalization of receptors and integrins.

• Receptor-mediated endocytosis. Macromolecules bound to membrane receptors (such as transferrin or low-density lipoprotein [LDL] receptors) are taken up at specialized regions of the plasma membrane called clathrin-coated pits. The receptors are efficiently internalized by mem brane invaginations driven by the associated clathrin matrix, eventually pinching off to form clathrin-coated vesicles. Trapped within these vesicles is also a gulp of the extracellular milieu (fluid-phase pinocytosis). The vesicles then rapidly lose their clathrin coating and fuse with an acidic intracellular structure called the early endosome; the endosomal vesicles undergo progressive maturation to late endosomes, ultimately fusing with lysosomes. In the acidic environment of the endosomes, LDL and transferrin receptors release their cargo (cholesterol and iron, respectively), which is then transported into the cytosol.

After release of bound ligand, some receptors recycle to the plasma membrane and are reused (e.g., transferrin and LDL receptors), while others are degraded within lysosomes (e.g., epidermal growth factor receptor). In the latter case, degradation after internalization results in receptor downregulation that limits receptor-mediated signaling. Defects in receptor-mediated transport of LDL underlie familial hypercholesterolemia, as described in Chapter 5.

Endocytosis requires recycling of internalized vesicles back to the plasma membrane (exocytosis) for another round of ingestion. This is critical, as a cell will typically ingest from the extracellular space the equivalent of 10% to 20% of its own cell volume each hour—amounting to 1% to 2% of its plasma membrane each minute! Without recycling, the plasma membrane would be rapidly depleted. Endo cytosis and exocytosis must therefore be tightly coupled to avoid large changes in plasma membrane area.

اخر الاخبار

اخبار العتبة العباسية المقدسة

العتبة العباسية المقدسة تنظّم محاضرة توعوية لطالبات كلية الأسوة للبنات في باكستان

الهيأة العليا لإحياء التراث تقيم دورة متخصّصة عن الفقه الكلامي

قسم التطوير يشرع بمقابلة المتقدمين للانضمام إلى أكاديمية التطوير الإداري

قسم الشؤون الفكرية يعلن انضمام جامعة كربلاء إلى المستودع الرقمي العراقي للأطاريح

المزيد

الآخبار الصحية

اختراع صيني.. لاصق يصلح كسور العظام خلال دقائق

اكتشاف حلقات عملاقة من الحمض النووي.. تقلل خطر السرطان

آباء أميركيون يطالبون بتنظيم روبوتات الدردشة لحماية الأطفال ؟

4 إشارات من القلب لا يجب تجاهلها أبدا

المزيد

الآخبار التكنلوجية

"تحليل المحادثات" يكشف كيف يستخدم الناس تشات جي بي تي

الدخان يكشف المستور.. التحنيط بدأ خارج مصر

مشهد مدهش للأرض من الفضاء.. جمجمة بيولوجية بعينين محدّقتين!

أول قطار يعمل بالهيدروجين في أميركا يدخل الخدمة رسميًا

المزيد

مواضيع ذات صلة

Cytoplasmic Structures in Prokaryotic Cell

Eukaryotic Cell Structure

Cell Differentiation

إنقسام الخلية النباتية Plant Cell Division

الرايبوسومات Ribosomes

Ameboid Movement

The Mitochondria Extract Energy From Nutrients

Synthesis of Cellular Structures by Endoplasmic Reticulum and Golgi Apparatus

Ingestion by the Cell—Endocytosis

Comparison of The Animal Cell with Precellular Forms of Life

Cell Cytoskeleton—Filament and Tubular Structures

Mitochondria