Paracellular transport

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Paracellular transport refers to the transfer of substances across an epithelium by passing through the intercellular space between the cells. [1] It is in contrast to transcellular transport, where the substances travel through the cell, passing through both the apical membrane and basolateral membrane. [2] [3]

The distinction has particular significance in renal physiology and intestinal physiology. Transcellular transport often involves energy expenditure whereas paracellular transport is unmediated and passive down a concentration gradient, [4] or by osmosis (for water) and solvent drag for solutes. [5] Paracellular transport also has the benefit that absorption rate is matched to load because it has no transporters that can be saturated.

In most mammals, intestinal absorption of nutrients is thought to be dominated by transcellular transport, e.g., glucose is primarily absorbed via the SGLT1 transporter and other glucose transporters. Paracellular absorption therefore plays only a minor role in glucose absorption, [6] although there is evidence that paracellular pathways become more available when nutrients are present in the intestinal lumen. [7] In contrast, small flying vertebrates (small birds and bats) rely on the paracellular pathway for the majority of glucose absorption in the intestine. [8] [9] This has been hypothesized to compensate for an evolutionary pressure to reduce mass in flying animals, which resulted in a reduction in intestine size and faster transit time of food through the gut. [10] [11]

Capillaries of the blood–brain barrier have only transcellular transport, in contrast with normal capillaries which have both transcellular and paracellular transport.

The paracellular pathway of transport is also important for the absorption of drugs in the gastrointestinal tract. The paracellular pathway allows the permeation of hydrophilic molecules that are not able to permeate through the lipid membrane by the transcellular pathway of absorption. This is particularly important for hydrophilic pharmaceuticals, which may not have affinity for membrane-bound transporters, and therefore may be excluded from the transcellular pathway. The vast majority of drug molecules are transported through the transcellular pathway, and the few which rely on the paracellular pathway of transportation typically have a much lower bioavailability; for instance, levothyroxine has an oral bioavailability of 40 to 80%, and desmopressin of 0.16%.

Structure of paracellular channels

Some claudins form tight junction-associated pores that allow paracellular ion transport. [12]

The tight junctions have a net negative charge, and are believed to preferentially transport positively charged molecules. Tight junctions in the intestinal epithelium are also known to be size-selective, such that large molecules (with molecular radii greater than about 4.5 Å) are excluded. [13] [14] [15] Larger molecules may also pass the intestinal epithelium via the paracellular pathway, although at a much slower rate and the mechanism of this transport via a "leak" pathway is unknown but may include transient breaks in the epithelial barrier.

Paracellular transport can be enhanced through the displacement of zona occludens proteins from the junctional complex by the use of permeation enhancers. Such enhancers include medium chain fatty acids (e.g. capric acid), chitosans, zona occludens toxin, etc.[ citation needed ]

Related Research Articles

In cellular biology, active transport is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses adenosine triphosphate (ATP), and secondary active transport that uses an electrochemical gradient. This process is in contrast to passive transport, which allows molecules or ions to move down their concentration gradient, from an area of high concentration to an area of low concentration, without energy.

<span class="mw-page-title-main">Passive transport</span> Transport that does not require energy

Passive transport is a type of membrane transport that does not require energy to move substances across cell membranes. Instead of using cellular energy, like active transport, passive transport relies on the second law of thermodynamics to drive the movement of substances across cell membranes. Fundamentally, substances follow Fick's first law, and move from an area of high concentration to an area of low concentration because this movement increases the entropy of the overall system. The rate of passive transport depends on the permeability of the cell membrane, which, in turn, depends on the organization and characteristics of the membrane lipids and proteins. The four main kinds of passive transport are simple diffusion, facilitated diffusion, filtration, and/or osmosis.

<span class="mw-page-title-main">Mediated transport</span> Transportation of substances via membrane

Mediated transport refers to transport mediated by a membrane transport protein. Substances in the human body may be hydrophobic, electrophilic, contain a positively or negatively charge, or have another property. As such there are times when those substances may not be able to pass over the cell membrane using protein-independent movement. The cell membrane is imbedded with many membrane transport proteins that allow such molecules to travel in and out of the cell. There are three types of mediated transporters: uniport, symport, and antiport. Things that can be transported are nutrients, ions, glucose, etc, all depending on the needs of the cell. One example of a uniport mediated transport protein is GLUT1. GLUT1 is a transmembrane protein, which means it spans the entire width of the cell membrane, connecting the extracellular and intracellular region. It is a uniport system because it specifically transports glucose in only one direction, down its concentration gradient across the cell membrane.

<span class="mw-page-title-main">Enterocyte</span> Type of intestinal cell

Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its surface area. This facilitates transport of numerous small molecules into the enterocyte from the intestinal lumen. These include broken down proteins, fats, and sugars, as well as water, electrolytes, vitamins, and bile salts. Enterocytes also have an endocrine role, secreting hormones such as leptin.

<span class="mw-page-title-main">Uniporter</span>

Uniporters, also known as solute carriers or facilitated transporters, are a type of membrane transport protein that passively transports solutes across a cell membrane. It uses facilitated diffusion for the movement of solutes down their concentration gradient from an area of high concentration to an area of low concentration. Unlike active transport, it does not require energy in the form of ATP to function. Uniporters are specialized to carry one specific ion or molecule and can be categorized as either channels or carriers. Facilitated diffusion may occur through three mechanisms: uniport, symport, or antiport. The difference between each mechanism depends on the direction of transport, in which uniport is the only transport not coupled to the transport of another solute.

<span class="mw-page-title-main">Cotransporter</span> Type of membrane transport proteins

Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable coupled or cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.

Bioenergetics is a field in biochemistry and cell biology that concerns energy flow through living systems. This is an active area of biological research that includes the study of the transformation of energy in living organisms and the study of thousands of different cellular processes such as cellular respiration and the many other metabolic and enzymatic processes that lead to production and utilization of energy in forms such as adenosine triphosphate (ATP) molecules. That is, the goal of bioenergetics is to describe how living organisms acquire and transform energy in order to perform biological work. The study of metabolic pathways is thus essential to bioenergetics.

<span class="mw-page-title-main">Tight junction</span> Structure preventing inter-cell leakage

Tight junctions, also known as occluding junctions or zonulae occludentes, are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epithelial cells. They also play a critical role maintaining the structure and permeability of endothelial cells. Tight junctions may also serve as leaky pathways by forming selective channels for small cations, anions, or water. The corresponding junctions that occur in invertebrates are septate junctions.

<span class="mw-page-title-main">Glucose transporter</span> Family of monosaccharide transport proteins

Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose across the plasma membrane, a process known as facilitated diffusion. Because glucose is a vital source of energy for all life, these transporters are present in all phyla. The GLUT or SLC2A family are a protein family that is found in most mammalian cells. 14 GLUTS are encoded by the human genome. GLUT is a type of uniporter transporter protein.

Intestinal permeability is a term describing the control of material passing from inside the gastrointestinal tract through the cells lining the gut wall, into the rest of the body. The intestine normally exhibits some permeability, which allows nutrients to pass through the gut, while also maintaining a barrier function to keep potentially harmful substances from leaving the intestine and migrating to the body more widely. In a healthy human intestine, small particles can migrate through tight junction claudin pore pathways, and particles up to 10–15 Å can transit through the paracellular space uptake route. There is some evidence abnormally increased intestinal permeability may play a role in some chronic diseases and inflammatory conditions. The most well understood condition with observed increased intestinal permeability is celiac disease.

<span class="mw-page-title-main">Transcytosis</span> Type of cellular transport

Transcytosis is a type of transcellular transport in which various macromolecules are transported across the interior of a cell. Macromolecules are captured in vesicles on one side of the cell, drawn across the cell, and ejected on the other side. Examples of macromolecules transported include IgA, transferrin, and insulin. While transcytosis is most commonly observed in epithelial cells, the process is also present elsewhere. Blood capillaries are a well-known site for transcytosis, though it occurs in other cells, including neurons, osteoclasts and M cells of the intestine.

Sodium-dependent glucose cotransporters are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron. They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron. If the plasma glucose concentration is too high (hyperglycemia), glucose passes into the urine (glucosuria) because SGLT are saturated with the filtered glucose.

<span class="mw-page-title-main">Vascular permeability</span>

Vascular permeability, often in the form of capillary permeability or microvascular permeability, characterizes the capacity of a blood vessel wall to allow for the flow of small molecules or even whole cells in and out of the vessel. Blood vessel walls are lined by a single layer of endothelial cells. The gaps between endothelial cells are strictly regulated depending on the type and physiological state of the tissue.

<span class="mw-page-title-main">Peptide transporter 1</span> Mammalian protein found in Homo sapiens

Peptide transporter 1 also known as solute carrier family 15 member 1 (SLC15A1) is a protein that in humans is encoded by SLC15A1 gene. PepT 1 is a solute carrier for oligopeptides. It functions in renal oligopeptide reabsorption and in the intestines in a proton dependent way, hence acting like a cotransporter.

<span class="mw-page-title-main">Intestinal epithelium</span> Single-cell layer lining the intestines

The intestinal epithelium is the single cell layer that form the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelial cells, it serves two main functions: absorbing useful substances into the body and restricting the entry of harmful substances. As part of its protective role, the intestinal epithelium forms an important component of the intestinal mucosal barrier. Certain diseases and conditions are caused by functional defects in the intestinal epithelium. On the other hand, various diseases and conditions can lead to its dysfunction which, in turn, can lead to further complications.

Transcellular transport involves the transportation of solutes by a cell through a cell. Transcellular transport can occur in three different ways active transport, passive transport, and transcytosis.

Buccal administration is a topical route of administration by which drugs held or applied in the buccal area diffuse through the oral mucosa and enter directly into the bloodstream. Buccal administration may provide better bioavailability of some drugs and a more rapid onset of action compared to oral administration because the medication does not pass through the digestive system and thereby avoids first pass metabolism.

The internal surface of the uterus is lined by uterine epithelial cells which undergo dramatic changes during pregnancy. The role of the uterine epithelial cells is to selectively allow the blastocyst to implant at a specific time. All other times of the cycle, these uterine epithelial cells are refractory to blastocyst implantation. Uterine epithelial cells have a similar structure in most species and the changes which occur in the uterine epithelial cells at the time of blastocyst implantation are also conserved among most species.

Larazotide is a synthetic eight amino acid peptide that functions as a tight junction regulator and reverses leaky junctions to their normally closed state. It is being studied in people with celiac disease.

Penetration enhancers are chemical compounds that can facilitate the penetration of active pharmaceutical ingredients (API) into or through the poorly permeable biological membranes. These compounds are used in some pharmaceutical formulations to enhance the penetration of APIs in transdermal drug delivery and transmucosal drug delivery. They typically penetrate into the biological membranes and reversibly decrease their barrier properties.

References

  1. ↑ "Calcium Adsorption". Citracal. Bayer. Archived from the original on 2006-03-07.
  2. ↑ Blystone R. "Epithelial Transcellular Transport". Trinity University. Archived from the original on 9 February 2007.
  3. ↑ Nosek TM. "Transport Across a Cell Layer: Transcellular Transport". Essentials of Human Physiology. Archived from the original on 2016-03-24.
  4. ↑ Barac-Nieto M. "Tubular Transport". Renal Physiology Tutorial Web Site. Department of Physiology. Kuwait University. Archived from the original on 14 February 2006.
  5. ↑ Hall, John E. (2020). "Passive Water Reabsorption by Osmosis Coupled Mainly to Sodium Reabsorption". Guyton and Hall textbook of medical physiology (Fourteenth ed.). Amsterdam. ISBN   9780323640039.{{cite book}}: CS1 maint: location missing publisher (link)
  6. ↑ Schwartz RM, Furne JK, Levitt MD (October 1995). "Paracellular intestinal transport of six-carbon sugars is negligible in the rat". Gastroenterology. 109 (4): 1206–1213. doi: 10.1016/0016-5085(95)90580-4 . PMID   7557087.
  7. ↑ Pappenheimer JR, Reiss KZ (1987). "Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat". The Journal of Membrane Biology. 100 (2): 123–136. doi:10.1007/BF02209145. PMID   3430569. S2CID   20716486.
  8. ↑ Lavin SR, Karasov WH (2008). "Allometry of paracellular absorption in birds". Physiological and Biochemical Zoology. 81 (5): 551–560. doi:10.1086/588176. PMID   18752419. S2CID   12228465.
  9. ↑ Price ER, Rott KH, Caviedes-Vidal E, Karasov WH (October 2014). "Paracellular nutrient absorption is higher in bats than rodents: integrating from intact animals to the molecular level". The Journal of Experimental Biology. 217 (Pt 19): 3483–3492. doi: 10.1242/jeb.105619 . hdl: 11336/14502 . PMID   25063860.
  10. ↑ Caviedes-Vidal E, McWhorter TJ, Lavin SR, Chediack JG, Tracy CR, Karasov WH (November 2007). "The digestive adaptation of flying vertebrates: high intestinal paracellular absorption compensates for smaller guts". Proceedings of the National Academy of Sciences of the United States of America. 104 (48): 19132–19137. Bibcode:2007PNAS..10419132C. doi: 10.1073/pnas.0703159104 . PMC   2141920 . PMID   18025481.
  11. ↑ Price ER, Brun A, Caviedes-Vidal E, Karasov WH (January 2015). "Digestive adaptations of aerial lifestyles". Physiology. 30 (1): 69–78. doi:10.1152/physiol.00020.2014. hdl: 11336/14497 . PMID   25559157.
  12. ↑ Anderson JM, Van Itallie CM (August 2009). "Physiology and function of the tight junction". Cold Spring Harbor Perspectives in Biology. 1 (2): a002584. doi:10.1101/cshperspect.a002584. PMC   2742087 . PMID   20066090.
  13. ↑ Chediack JG, Caviedes-Vidal E, Fasulo V, Yamin LJ, Karasov WH (April 2003). "Intestinal passive absorption of water-soluble compounds by sparrows: effect of molecular size and luminal nutrients". Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology. 173 (3): 187–197. doi:10.1007/s00360-002-0314-8. PMID   12743721. S2CID   26845857.
  14. ↑ Turner JR, Buschmann MM, Romero-Calvo I, Sailer A, Shen L (December 2014). "The role of molecular remodeling in differential regulation of tight junction permeability". Seminars in Cell & Developmental Biology. 36: 204–212. doi:10.1016/j.semcdb.2014.09.022. PMC   4253049 . PMID   25263012.
  15. ↑ Caviedes-Vidal E, McWhorter TJ, Lavin SR, Chediack JG, Tracy CR, Karasov WH (November 2007). "The digestive adaptation of flying vertebrates: high intestinal paracellular absorption compensates for smaller guts". Proceedings of the National Academy of Sciences of the United States of America. 104 (48): 19132–19137. Bibcode:2007PNAS..10419132C. doi: 10.1073/pnas.0703159104 . PMC   2141920 . PMID   18025481.
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