Movement through the cell membrane occurs in essentially two ways: passively, without an expenditure of energy, or actively, using energy-consuming processes. The cell membrane can also engulf a particle, forming a membrane-coated vesicle; this membrane-coated vesicle is moved into the cell by endocytosis or out of the cell by exocytosis.
Passive movement of particles or ions across the cell membrane is directly influenced by chemical or electrical gradients and does not require an expenditure of energy. A difference in the number of particles on either side of the membrane creates a chemical gradient and a difference in charged particle or ions creates an electrical gradient. Chemical and electrical gradients are often linked and are called electrochemical gradients.
Diffusion. Diffusion refers to the process by which molecules and other particles in a solution become widely dispersed and reach a uniform concentration because of energy created by their spontaneous kinetic movements (Fig. 4.14A). Electrolytes and other substances move from an area of higher to an area of lower concentration. With ions, diffusion is affected by energy supplied by their electrical charge. Lipid-soluble molecules such as oxygen, carbon dioxide, alcohol, and fatty acids become dissolved in the lipid matrix of the cell membrane and diffuse through the membrane in the same manner that diffusion occurs in water. Other substances diffuse through minute pores of the cell membrane. The rate of movement depends on how many particles are available for diffusion and the velocity of the kinetic movement of the particles. The number of openings in the cell membrane through which the particles can move also determines transfer rates. Temperature changes the motion of the particles; the greater the temperature, the greater is the thermal motion of the molecules. Thus, diffusion increases in proportion to increased temperature.
Osmosis. Most cell membranes are semipermeable in that they are permeable to water but not to all solute particles. Water moves through water channels (aquaporins) in a semi-permeable membrane along a concentration gradient, moving from an area of higher to one of lower concentration (see Fig. 4.14B). This process is called osmosis, and the pressure that water generates as it moves through the membrane is called osmotic pressure.
Osmosis is regulated by the concentration of nondiffusible particles on either side of a semipermeable membrane. When there is a difference in the concentration of particles, water moves from the side with the lower concentration of particles and higher concentration of water to the side with the higher concentration of particles and lower concentration of water. The movement of water continues until the concentration of particles on both sides of the membrane is equally diluted or until the hydrostatic (osmotic) pressure created by the movement of water opposes its flow.
Facilitated Diffusion. Facilitated diffusion occurs through a transport protein that is not linked to metabolic energy (see Fig. 4.14C). Some substances, such as glucose, cannot pass unassisted through the cell membrane because they are not lipid soluble or are too large to pass through the membrane’s pores. These substances combine with special transport proteins at the membrane’s outer surface, are carried across the membrane attached to the transporter, and then released on the inside of the membrane. In facilitated diffusion, a sub-stance can move only from an area of higher concentration to one of lower concentration. The rate at which a substance moves across the membrane because of facilitated diffusion depends on the difference in concentration between the two sides of the membrane. Also important are the availability of transport proteins and the rapidity with which they can bind and release the substance being transported. It is thought that insulin, which facilitates the movement of glucose into cells, acts by increasing the availability of glucose transporters in the cell membrane.
Active Transport and Cotransport
Active transport mechanisms involve the expenditure of energy. The process of diffusion describes particle movement from an area of higher concentration to one of lower concentration, resulting in an equal distribution across the cell membrane. Sometimes, however, different concentrations of a substance are needed in the intracellular and extracellular fluids. For example, to function, a cell requires a much higher intracellular concentration of potassium ions than is present in the extracellular fluid, while maintaining a much lower intra-cellular concentration of sodium ions than the extracellular fluid. In these situations, energy is required to pump the ions “uphill” or against their concentration gradient. When cells use energy to move ions against an electrical or chemical gradient, the process is called active transport.
The active transport system studied in the greatest detail is the sodium–potassium (Na+/K+)–ATPase pump (see Fig. 4.14D). This pump moves sodium from inside the cell to the extracellular region, the pump also returns potassium to the inside, of the cell. Energy used to pump sodium out of the cell and potassium into the cell is obtained by splitting and releasing energy from the high-energy phosphate bond in ATP by the enzyme ATPase. Were it not for the activity of the Na+/K+–ATPase pump, the osmotically active sodium particles would accumulate in the cell, causing cellular swelling because of an accompanying influx of water.
Two types of active transport systems exist: primary active transport and secondary active transport. In primary active transport, the source of energy (e.g., ATP) is used directly in the transport of a substance. Secondary active transport mechanisms harness the energy derived from the primary active transport of one substance, usually sodium, for the cotransport of a second substance. For example, when sodium ions are actively transported out of a cell by primary active transport, a large concentration gradient develops (i.e., high concentration on the outside and low on the inside). This concentration gradient represents a large storehouse of energy because sodium ions are always attempting to diffuse into the cell. Similar to facilitated diffusion, secondary transport mechanisms use membrane transport proteins. These proteins have two binding sites, one for sodium and the other for the substance undergoing secondary transport. Secondary transport systems are classified into two groups: cotransport or symport systems, in which the sodium ion and the solute are transported in the same direction, and countertransport or antiport systems, in which the sodium ion and the solute are transported in the opposite direction (Fig. 4.15). An example of cotransport occurs in the intestine, where the absorption of glucose and amino acids is coupled with sodium transport.
Endocytosis and Exocytosis
Endocytosis is the process by which cells engulf materials from their surroundings. It includes pinocytosis and phagocytosis. Pinocytosis involves the ingestion of small solid or fluid particles. The particles are engulfed into small, membrane-surrounded vesicles for movement into the cytoplasm. The process of pinocytosis is important in the transport of proteins and strong solutions of electrolytes (see Fig. 4.14E).
Phagocytosis literally means “cell eating” and can be compared with pinocytosis, which means “cell drinking.” It involves the engulfment and subsequent killing or degradation of microorganisms or other particulate matter. During phagocytosis, a particle contacts the cell surface and is surrounded on all sides by the cell membrane, forming a phagocytic vesicle or phagosome. Once formed, the phagosome breaks away from the cell membrane and moves into the cytoplasm, where it eventually fuses with a lysosome, allowing the ingested material to be degraded by lysosomal enzymes. Certain cells, such as macrophages and polymorphonuclear leukocytes (neutrophils), are adept at engulfing and disposing of invading organisms, damaged cells, and unneeded extracellular constituents.
Receptor-mediated endocytosis involves the binding of substances such as low-density lipoproteins to a receptor on the cell surface. Binding of a ligand (i.e., a substance with a high affinity for a receptor) to its receptor normally causes widely distributed receptors to accumulate in clathrincoated pits. An aggregation of special proteins on the cytoplasmic side of the pit causes the coated pit to invaginate and pinch off, forming a clathrin-coated vesicle that carries the ligand and its receptor into the cell.
Exocytosis is the mechanism for the secretion of intracellular substances into the extracellular spaces. It is the reverse of endocytosis in that a secretory granule fuses to the inner side of the cell membrane and an opening is created in the cell membrane. This opening allows the contents of the granule to be released into the extracellular fluid. Exocytosis is important in removing cellular debris and releasing substances, such as hormones, synthesized in the cell.
During endocytosis, portions of the cell membrane become an endocytotic vesicle. During exocytosis, the vesicular membrane is incorporated into the plasma membrane. In this way, cell membranes can be conserved and reused.
The electrical charge on small ions such as sodium and potassium makes it difficult for these ions to move across the lipid layer of the cell membrane. However, rapid movement of these ions is required for many types of cell functions, such as nerve activity. This is accomplished by facilitated diffusion through selective ion channels. Ion channels are integral proteins that span the width of the cell membrane and are normally com- posed of several polypeptides or protein subunits that form a gating system. Specific stimuli cause the protein subunits to undergo conformational changes to form an open channel or gate through which the ions can move (Fig. 4.16). In this way, ions do not need to cross the lipid-soluble portion of the membrane but can remain in the aqueous solution that fills the ion channel. Ion channels are highly selective; some channels allow only for passage of sodium ions, and others are selective for potassium, calcium, or chloride ions. Specific interactions between the ions and the sides of the channel can produce an extremely rapid rate of ion movement. For example, ion channels can become negatively charged, promoting the rapid movement of positively charged ions.
The plasma membrane contains two basic groups of ion channels: leakage channels and gated channels. Leakage channels are open even in the unstimulated state, whereas gated channels open and close in response to specific stimuli. Three main types of gated channels are present in the plasma membrane: voltage-gated channels, which have electrically operated channels that open when the membrane potential changes beyond a certain point; ligand-gated channels, which are chemically operated and respond to specific receptor-bound ligands, such as the neurotransmitter acetylcholine; and mechanically gated channels, which open or close in response to such mechanical stimulations as vibrations, tissue stretching, or pressure (see Fig. 4.16).