Human Biochemistry, Volume 2 - Murray R. 1993

Biochemistry of Intracellular and Intercellular Communication
Membranes: Structure, Assembly, and Function
Transmembrane Movement of Macromolecules

Macromolecules are also transported across Cell/30.html">The Plasma Membrane. The process by which Cells capture large molecules is called endocytosis. Some of these molecules (such as Polysaccharides, Proteins, and polynucleotides) serve as a source of nutrients. Endocytosis also makes it possible to regulate the content of specific membrane components, particularly Hormone Receptors. Furthermore, endocytosis can be utilized for a more detailed Study of Cellular Functions. Cells of one type can be transformed using DNA from another type, thereby altering their functional profile or phenotype. Such experiments frequently employ specific genes, providing a unique opportunity to investigate the mechanisms of their regulation. Cellular transformation with DNA is mediated by endocytosis, which is precisely how DNA enters The Cell. Transformation is usually performed in the presence of calcium phosphate, as Ca²⁺ stimulates both endocytosis and DNA precipitation, thereby facilitating its cellular uptake via endocytosis. Macromolecules exit the cell via exocytosis. Both Endocytosis and Exocytosis involve The formation of vesicles that either fuse with the plasma membrane or bud off from it.

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Fig. 42.19. Two Types of endocytosis. Endocytic vesicles (V) are formed at the sites of plasma membrane invagination. Fluid-phase pinocytosis (A) is a random, non-directed process. Receptor-mediated pinocytosis (B) is selective and proceeds via the formation of coated pits (CP) lined with the protein clathrin (amorphous material) and coated vesicles (CV). Its Specificity is ensured by receptors (black rectangles) specific for various molecules.

Endocytosis

In all Eukaryotic cells, a portion of the plasma membrane is continuously internalized into the Cytoplasm. This occurs As a result of the invagination of a plasma membrane fragment, the formation of an endocytic vesicle, the constriction of the vesicle neck, and its pinching off into the cytoplasm along with its contents (Fig. 42.19). Subsequently, these vesicles can fuse with other membrane structures, thereby transferring their contents to other cellular compartments or even back to the extracellular space. Most endocytic vesicles fuse with primary Lysosomes to form secondary lysosomes, which contain hydrolytic Enzymes and function as specialized Organelles. Macromolecules are digested within them into Amino Acids, simple sugars, and NUCLEOTIDES, which diffuse out of the vesicles and are utilized in the cytoplasm. Endocytosis requires: 1) energy, typically derived from ATP; 2) extracellular Ca²⁺; 3) contractile elements within the cell (likely microfilament systems).

Endocytosis can be subdivided into two main types. Phagocytosis is carried out exclusively by specialized cells, such as macrophages and granulocytes. During phagocytosis, large particles such as Viruses, Bacteria, cells, or cellular debris are engulfed. Macrophages are exceptionally active in this regard and can internalize a volume equivalent to 25% of their own volume within 1 hour. This entails the internalization of 3% of their plasma membrane every minute, or the entire membrane every 30 minutes.

Pinocytosis is a property of all cells. Through this process, the cell takes up fluids and dissolved solutes. This process can also be subdivided into two types. Fluid-phase pinocytosis is a non-selective process in which The amount of solute taken up within vesicles is simply proportional to its concentration in the extracellular fluid. Such vesicles are formed with remarkable activity. For instance, in fibroblasts, The rate of plasma membrane internalization is 1/3 of that characteristic of macrophages. In this case, the membrane is consumed faster than it is synthesized. At the same time, the surface area and cell volume do not change dramatically, indicating that the membrane is replenished via exocytosis or recycled at the same rate at which it is consumed.

Another type of pinocytosis, adsorptive pinocytosis, is a selective, Ligand-mediated process. It is primarily responsible for the uptake of macromolecules for which a limited number of binding sites exist on the plasma membrane. These high-affinity receptors selectively concentrate ligands from the medium while minimizing the uptake of fluid and unbound dissolved molecules, thereby significantly increasing the efficiency of specific molecular delivery into the cell. Vesicles formed during adsorptive pinocytosis originate at sites of invaginations (pits) coated on their cytoplasmic side with a fibrous material. This material is typically clathrin (likely a peripheral membrane protein). Coated pits can occupy up to 2% of the surface area of certain cells.

Coated pits, housing their respective receptors, mediate the internalization of, for example, low-density Lipoproteins (LDLs) and their receptors (see Chapter 26). Endocytic vesicles containing LDLs and their receptors fuse with lysosomes within the cell. The receptors are released and recycled back to the plasma membrane surface, whereas the LDL apoprotein is degraded and the corresponding Cholesterol ester is metabolized. The synthesis of LDL receptors is regulated by secondary or tertiary products of pinocytosis—that is, substances generated during LDL METABOLISM, such as cholesterol. Impairments in LDL receptor formation and internalization are of major Biomedical Significance (Chapter 26).

Adsorptive pinocytosis also mediates the uptake of other macromolecules, including certain Hormones. This process yields receptosomes—vesicles that do not fuse with lysosomes but instead deliver their contents to other intracellular compartments, such as the Golgi apparatus.

For adsorptive pinocytosis of extracellular Glycoproteins to occur, the latter must contain a specific carbohydrate residue designated for recognition. Such signal residues bind to membrane receptor molecules, which perform the same function as the LDL receptor. Hepatocytes feature a cell-surface galactosyl receptor that mediates the adsorptive pinocytosis of sialoglycoproteins. Acid Hydrolases taken up by fibroblasts via adsorptive pinocytosis are recognized owing to a mannose-6-phosphate residue. Interestingly, this residue appears to play a critical role in the intracellular targeting of hydrolases to lysosomes (see Chapter 54).

Receptor-mediated endocytosis has its dark side, as viruses responsible for certain diseases—such as hepatitis (causing Liver damage), poliomyelitis (affecting motor Neurons), and AIDS (targeting T cells)—hijack this exact mechanism to invade cells. Furthermore, the Toxic effects of iron can also manifest as a result of its excessive uptake driven by endocytosis.

Exocytosis

Most cells release macromolecules into the external environment via exocytosis. This process also plays a role in membrane turnover, whereby membrane components synthesized in the Golgi apparatus are delivered to the plasma membrane via vesicles. The trigger for exocytosis is often provided by a hormone that, upon binding to a cell-surface receptor, induces local and reversible fluctuations in Ca²⁺ concentration that initiate exocytosis. Figure 4.20 schematically illustrates the processes of exocytosis and endocytosis.

Fig. 42.20. Comparison of endocytosis and exocytosis mechanisms. Exocytosis involves the fusion of two inner monolayers facing the cytoplasm, whereas endocytosis involves the fusion of the outer monolayers.

Substances released via exocytosis can be divided into three categories: 1) substances that bind to the cell surface and become peripheral proteins, such as Antigens; 2) substances incorporated into the Extracellular matrix, such as Collagen and glycosaminoglycans; 3) substances secreted into the extracellular environment that serve as signaling molecules for other cells. Insulin, parathyroid hormone, and catecholamines are packaged into granules and undergo intracellular maturation before being released upon appropriate stimulation (Chapters 47, 49, and 51).