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Intestinal Nucleoside Transporters: Function, Expression, and Regulation

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ABSTRACT

The gastrointestinal tract is the absorptive organ for nutrients found in foods after digestion. Nucleosides and, to a lesser extent nucleobases, are the late products of nucleoprotein digestion. These metabolites are absorbed by nucleoside (and nucleobase) transporter (NT) proteins. NTs are differentially distributed along the gastrointestinal tract showing also polarized expression in epithelial cells. Concentrative nucleoside transporters (CNTs) are mainly located at the apical side of enterocytes, whereas equilibrative nucleoside transporters (ENTs) facilitate the basolateral efflux of nucleosides and nucleobases to the bloodstream. Moreover, selected nucleotides and the bioactive nucleoside adenosine act directly on intestinal cells modulating purinergic signaling. NT‐polarized insertion is tightly regulated. However, not much is known about the modulation of intestinal NT function in humans, probably due to the lack of appropriate cell models retaining CNT functional expression. Thus, the possibility of nutritional regulation of intestinal NTs has been addressed using animal models. Besides the nutrition‐related role of NT proteins, orally administered drugs also need to cross the intestinal barrier, this event being a major determinant of drug bioavailability. In this regard, NT proteins might also play a role in pharmacology, thereby allowing the absorption of nucleoside‐ and nucleobase‐derived drugs. The relative broad selectivity of these membrane transporters also suggests clinically relevant drug‐drug interactions when using combined therapies. This review focuses on all these physiological and pharmacological aspects of NT protein biology. © 2017 American Physiological Society. Compr Physiol 8:1003‐1017, 2018.

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Figure 1. Figure 1. SLC28, SLC29, and SLC43A3 mRNA expression along the gastrointestinal system. Data obtained, with permission, from the public repository EMBL‐EBI Expression Atlas. Samples from 122 individuals representing different tissues were analyzed by RNA‐seq of coding RNA (Expression Atlas—E‐MTAB‐2836).
Figure 2. Figure 2. Intestinal simplified purinome machinery depicting the dual role of hCNT proteins in nucleoside absorption and purinergic signaling. Luminal nucleotides in either physiological (arising from diet and microbiota) or pathophysiological conditions such as inflammation (arising from polymorphonuclear leukocytes—PMNs—and platelets) will be degraded by various ectonucleotidases (CD39, CD73, among other), ultimately yielding adenosine, among other nucleosides. Adenosine is a bioactive nucleoside, which triggers purinergic signaling via P1 receptors. In small intestine, adenosine will be removed from the lumen mostly by the high‐affinity concentrative nucleoside transporter hCNT2. Although hCNT3 is also a high‐affinity adenosine transporter it does not seem to be expressed at significant levels in small intestine, although it could contribute to remove adenosine at distal segments of the gastrointestinal tract (i.e., colon). hCNT1 is not an adenosine transporter, although this nucleoside can bind to hCNT1 with still unknown effects on cell physiology.


Figure 1. SLC28, SLC29, and SLC43A3 mRNA expression along the gastrointestinal system. Data obtained, with permission, from the public repository EMBL‐EBI Expression Atlas. Samples from 122 individuals representing different tissues were analyzed by RNA‐seq of coding RNA (Expression Atlas—E‐MTAB‐2836).


Figure 2. Intestinal simplified purinome machinery depicting the dual role of hCNT proteins in nucleoside absorption and purinergic signaling. Luminal nucleotides in either physiological (arising from diet and microbiota) or pathophysiological conditions such as inflammation (arising from polymorphonuclear leukocytes—PMNs—and platelets) will be degraded by various ectonucleotidases (CD39, CD73, among other), ultimately yielding adenosine, among other nucleosides. Adenosine is a bioactive nucleoside, which triggers purinergic signaling via P1 receptors. In small intestine, adenosine will be removed from the lumen mostly by the high‐affinity concentrative nucleoside transporter hCNT2. Although hCNT3 is also a high‐affinity adenosine transporter it does not seem to be expressed at significant levels in small intestine, although it could contribute to remove adenosine at distal segments of the gastrointestinal tract (i.e., colon). hCNT1 is not an adenosine transporter, although this nucleoside can bind to hCNT1 with still unknown effects on cell physiology.

 

Teaching Material

M. Pastor-Anglada, N. Urtasun, S. Pérez-Torras. Intestinal Nucleoside Transporters: Function, Expression, and Regulation. Compr Physiol 8: 2018, 1003-1017.

Didactic Synopsis

Major Teaching Points:

  1. Nucleosides and nucleobases are nutrients, which might become essential for health in certain conditions such as early child development. These nutrients must be absorbed in the intestine.
  2. Two protein families, concentrative (hCNT) and equilibrative (hENT) transporters contribute to nucleoside absorption. Deciphering how these proteins are expressed and regulated in polarized epithelia and along the gastrointestinal tract is necessary to understand how nucleotide nutrition in humans occurs.
  3. Apical expression of concentrative transporters and basolateral equilibrative transporters allow vectorial flux of nucleosides and nucleobases across the intestinal barrier.
  4. hENT proteins are regulated by proliferative stimulus whereas hCNT expression is associated with differentiation.
  5. Selected NT proteins are also adenosine transporters, thereby being able to modulate purinergic signaling.
  6. The study of NT proteins along the gastrointestinal tract is also of pharmacological relevance because NTs are also drug transporters.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching points: Nucleosides are nutrients and precursors of crucial macromolecules for life, such as nucleic acids. Absorption of nucleosides from the diet requires the coordinated work of different proteins, generally called “nucleoside transporters” (NTs). This figure shows where these proteins are expressed along the gastrointestinal tract to illustrate where efficient nucleoside absorption takes place.

Figure 2 Teaching points: One type of nucleoside, known as adenosine, can also modulate various physiological events, such as intestinal motility and adaptation to pathophysiological conditions associated with inflammation. In this regard, the amount of luminal adenosine needs to be tightly controlled, being NT proteins not only mediators of nutrient uptake but also modulators of adenosine-mediated effects.

 


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How to Cite

Marçal Pastor‐Anglada, Nerea Urtasun, Sandra Pérez‐Torras. Intestinal Nucleoside Transporters: Function, Expression, and Regulation. Compr Physiol 2018, 8: 1003-1017. doi: 10.1002/cphy.c170039