Paracellular transport

For the complementary transport route, see Transcellular transport.

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]}

References

1. . Citracal. Bayer. Archived from the original on 2006-03-07.
2. Blystone R. . Trinity University. Archived from the original on 9 February 2007.
3. Nosek TM. . Essentials of Human Physiology. Archived from the original on 2016-03-24.
4. Barac-Nieto M. . 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.
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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.