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Transcellular Transport

المؤلف:  Harvey Lodish, Arnold Berk, Chris A. Kaiser, Monty Krieger, Anthony Bretscher, Hidde Ploegh, Angelika Amon, and Kelsey C. Martin.

المصدر:  Molecular Cell Biology

الجزء والصفحة:  8th E , P508-510

2026-05-21

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 Here we extend this concept by focusing on the transport of several types of molecules and ions across polarized cells, which are cells that are asymmetric (have different “sides”) and thus have biochemically distinct regions of the plasma membrane. A particularly well-studied class of polarized cells includes many of the epithelial cells that form sheet-like layers (epithelia) covering most external and internal surfaces of body organs. Like many epithelial cells, an intestinal epithelial cell involved in absorbing nutrients from the gastrointestinal tract has a plasma membrane organized into two major discrete regions: the surface that faces the outside of the organism, called the apical, or top, surface, and the sur face that faces the inside of the organism (or the bloodstream facing side), called the basolateral surface, which is composed of the basal and lateral surfaces of the cell.

Specialized regions of the epithelial-cell plasma mem brane, called tight junctions, separate the apical and basolateral membranes and prevent many, but not all, water-soluble substances on one side from moving across to the other side through the extracellular space between cells. For this reason, absorption of many nutrients from the intestinal lumen across the epithelial cell layer and eventually into the blood occurs by a two-stage process called transcellular transport: import of molecules through the plasma membrane on the apical side of intestinal epithelial cells and their export through the plasma membrane on the basolateral (blood-facing) side (Figure 1). The apical portion of the plasma membrane, which faces the intestinal lumen, is specialized for absorption of sugars, amino acids, and other molecules that are produced from food by multiple digestive enzymes.

Fig1. Transcellular transport of glucose from the intestinal lumen into the blood. The Na+/K+ ATPase in the basolateral surface membrane generates Na+ and K+ concentration gradients (step 1). The outward movement of K+ ions through nongated K+ channels generates an inside-negative membrane potential across the entire plasma membrane. Both the Na+ concentration gradient and the membrane potential are used to drive the uptake of glucose from the intestinal lumen by the two-Na+/one-glucose symporter located in the apical surface membrane (step 2). Glucose leaves the cell via facilitated transport catalyzed by GLUT2, a glucose uniporter located in the basolateral membrane (step 3).

Multiple Transport Proteins Are Needed to Move Glucose and Amino Acids Across Epithelia

Figure 1, which depicts the proteins that mediate ab sorption of glucose from the intestinal lumen into the blood, illustrates the important concept that different types of proteins are localized to the apical and basolateral membranes of epithelial cells. In the first stage of this process, a two Na+/one-glucose symporter located in the apical membrane imports glucose, against its concentration gradient, from the intestinal lumen across the apical surface of the epithelial cells. As noted above, this symporter couples the energetically unfavorable inward movement of one glucose molecule to the energetically favorable inward transport of two Na+ ions (see Figure 11-26). In the steady state, all the Na+ ions transported from the intestinal lumen into the cell during Na+/glucose symport, or the similar process of Na+/amino acid symport that also takes place on the apical membrane, are pumped out across the basolateral membrane, which faces the blood. Thus the low intracellular Na+ concentration is maintained. The Na+/K+ ATPase that accomplishes this pumping is found exclusively in the basolateral mem brane of intestinal epithelial cells. The coordinated operation of these two transport proteins allows uphill movement of glucose and amino acids from the intestine into the cell. This first stage in transcellular transport is ultimately powered by ATP hydrolysis by the Na+/K+ ATPase.

In the second stage, the glucose and amino acids concentrated inside intestinal cells by apical symporters are ex ported down their concentration gradients into the blood via uniport proteins in the basolateral membrane. In the case of glucose, this movement is mediated by GLUT2 (see Figure 1). As noted earlier, this GLUT isoform has a relatively low affinity for glucose but increases its rate of transport substantially when the glucose gradient across the membrane rises.

The net result of this two-stage process is movement of Na+ ions, glucose, and amino acids from the intestinal lumen across the intestinal epithelium into the extracellular medium that surrounds the basolateral surface of intestinal epithelial cells, and eventually into the blood. Tight junctions between the epithelial cells prevent these molecules from diffusing back into the intestinal lumen. The increased osmotic pressure created by transcellular transport of salt, glucose, and amino acids across the intestinal epithelium draws water from the intestinal lumen, mainly through the tight junctions, into the extracellular medium that sur rounds the basolateral surface; aquaporins do not appear to play a major role. In a sense, salts, glucose, and amino acids “carry” the water along with them.

Simple Rehydration Therapy Depends on the Osmotic Gradient Created by Absorption of Glucose and Na+

An understanding of osmosis and the intestinal absorption of salt and glucose forms the basis for a simple therapy that saves millions of lives each year, particularly in developing countries. In these countries, cholera and other intestinal pathogens are major causes of death for young children. A toxin released by these bacteria activates chloride secretion from the apical surfaces of intestinal epithelial cells into the lumen; water follows osmotically, and the resultant massive loss of water causes diarrhea, dehydration, and ultimately death. A cure demands not only killing the bacteria with antibiotics but also rehydration: replacement of the water that is lost from the blood and other tissues.

Simply drinking water does not help because it is excreted from the gastrointestinal tract almost as soon as it enters. However, as we have just learned, the coordinated transport of glucose and Na+ across the intestinal epithelium creates a transepithelial osmotic gradient, forcing water to move from the intestinal lumen across the epithelial cell layer and ultimately into the blood. Thus giving affected children a solution of sugar and salt to drink (but not sugar or salt alone) causes increased sodium and sugar transepithelial transport and, consequently, increased osmotic flow of water into the blood from the intestinal lumen, leading to rehydration. Simi lar sugar-salt solutions are the basis of popular drinks used by athletes to get sugar as well as water into the body quickly and efficiently.

Parietal Cells Acidify the Stomach Contents While Maintaining a Neutral Cytosolic pH

The mammalian stomach contains a 0.1 M solution of hydrochloric acid (HCl). This strongly acidic medium kills many ingested pathogens and denatures many ingested proteins so that they can be degraded by proteolytic enzymes (e.g., pepsin) that function at acidic pH. Hydrochloric acid is secreted into the stomach by specialized epithelial cells called parietal cells (also known as oxyntic cells) in the stomach lining. These cells contain a H+/K+ ATPase in the apical membrane (which faces the stomach lumen) that generates a 1-million-fold H+ concentration gradient: pH ∼1.0 in the stomach lumen versus pH ∼7.2 in the cell cytosol. This P-class ATP-powered ion pump is similar in structure and function to the plasma-membrane Na+/K+ ATPase discussed earlier. The numerous mitochondria in parietal cells produce abundant ATP for use by the H+/K+ ATPase.

If parietal cells simply exported H+ ions in exchange for K+ ions, the loss of protons would lead to a rise in the con centration of OH⁻ ions in the cytosol and thus a marked increase in cytosolic pH. (Recall that [H+] × [OH−] is always is a constant, 10⁻¹⁴ M2.) Parietal cells avoid this rise in cytosolic pH in conjunction with acidification of the stomach lumen by using Cl⁻/HCO3⁻ antiporters in the basolateral membrane to export the excess OH⁻ ions from the cytosol to the blood. As noted earlier, these anion antiporters are activated at high cytosolic pH.

The overall process by which parietal cells acidify the stomach lumen is illustrated in Figure2. In a reaction catalyzed by carbonic anhydrase, the excess cytosolic OH⁻ combines with CO2 that diffuses in from the blood, forming HCO3⁻. This bicarbonate ion is exported across the basolateral membrane (and ultimately into the blood) by the Cl⁻/ HCO3⁻ antiporter in exchange for a Cl⁻ ion. The Cl⁻ ions then exit through Cl⁻ channels in the apical membrane, entering the stomach lumen. To preserve electroneutrality, each Cl⁻ ion that moves into the stomach lumen across the apical membrane is accompanied by a K+ ion that moves outward through a separate K+ channel. In this way, the excess K+ ions pumped inward by the H+/K+ ATPase are returned to the stomach lumen, thus maintaining the normal intracellular K+ concentration. The net result is secretion of equal amounts of H+ and Cl⁻ ions (i.e., HCl) into the stomach lumen, while the pH of the cytosol remains neutral and the excess OH⁻ ions, as HCO3⁻, are transported into the blood, where the change in pH is minimal.

Fig2. Acidification of the stomach lumen by parietal cells in the gastric lining. The apical membrane of parietal cells contains a H+/K+ ATPase (a P-class pump) as well as Cl⁻ and K+ channels. Note the cyclic K+ transport across the apical membrane: K+ ions are pumped inward by the H+/K+ ATPase and exit via a K+ channel. The basolateral membrane contains an anion antiporter that exchanges HCO3⁻ and Cl⁻ ions. The combined operation of these four different transport proteins and carbonic anhydrase acidifies the stomach lumen while maintaining the neutral pH of the cytosol.

Bone Resorption Requires the Coordinated Function of a V-Class Proton Pump and a Specific Chloride Channel

Net bone growth in mammals subsides just after puberty, but a finely balanced, highly dynamic process of disassembly (resorption) and reassembly (bone formation) goes on throughout adulthood. Such continual bone remodeling permits the repair of damaged bones and can release calcium, phosphate, and other ions from mineralized bone into the blood for use elsewhere in the body.

Osteoclasts, the bone-dissolving cells, are macrophages, a type of cells best known for their role in protecting the body from infections. Osteoclasts are polarized cells that adhere to bone and form specialized, very tight seals between themselves and the bone, creating an enclosed extracellular space (Figure 3). An adhered osteoclast then secretes into this space a corrosive mixture of HCl and proteases that dissolves the inorganic components of the bone into Ca2+ and phosphate and digests its protein components. The mechanism of HCl secretion is similar to that used by the stomach to generate digestive juice (see Figure 2). As in gastric HCl secretion, carbonic anhydrase and an anion antiporter are important for osteoclast function. Osteoclasts employ a V-class proton pump to export H+ ions into the bone-facing space, rather than the P-class H+/K+ pump used by gastric epithelial cells.

Fig3. Dissolution of bone by polarized osteoclast cells requires a V-class proton pump and the ClC-7 chloride channel. The osteoclast plasma membrane is divided into two domains separated by the tight seal between a ring of membrane and the bone surface. The membrane domain facing the bone contains V-class proton pumps and ClC-7 Cl− channels. The opposing membrane domain contains anion antiporters that exchange HCO3 − and Cl− ions. The combined operation of these three transport proteins and carbonic anhydrase acidifies the enclosed space and allows bone resorption while maintaining the neutral pH of the cytosol. See R. Planells-Cases and T. Jentsch, 2009, Biochim. Biophys. Acta 1792:173 for discussion of ClC-7.

The rare hereditary disease osteopetrosis, marked by increased bone density, is due to abnormally low bone resorption. Many patients have mutations in the gene encoding TCIRG1, a subunit of the osteoclast V-class proton pump, whose action is required to acidify the space between the osteoclast and the bone. Other patients have mutations in the gene encoding ClC-7, the chloride channel localized to the domain of the osteoclast plasma membrane that faces the space near the bone. As with lysosomes, in the absence of a chloride channel, the proton pump cannot acidify the enclosed extracellular space, and thus bone re sorption is defective.