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Chapter 14 : Physiological Regulation of Gastrointestinal Ion Transport

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Abstract:

This chapter describes the normal mechanisms whereby fluid is secreted and absorbed along the length of the gastrointestinal tract, and the regulatory pathways that govern these processes. The chapter discusses the precise transport mechanisms that mediate the flux of electrolytes and other solutes in the small and large intestines. All the transport mechanisms discussed in the chapter are active, in that they result in the transepithelial transport of the solute of interest against existing electrochemical gradients. Intestinal epithelial ion transport is regulated via complex pathways that are still not fully understood. Regulation can be divided into two complementary mechanisms: (i) an intercellular mechanism consisting of stimulation of the epithelium by mediators released from nerves, endocrine cells, and other effector cells and (ii) an intracellular mechanism where second messengers initiate signal transduction pathways within the epithelial cells themselves. Ultimately, regulatory mechanisms impinge on the membrane transporters. Ion movement across membranes can be accomplished by three distinct classes of transport mechanisms: carriers, pumps, and channels.

Citation: Barrett K, Bertelsen L. 2003. Physiological Regulation of Gastrointestinal Ion Transport, p 241-266. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch14

Key Concept Ranking

Integral Membrane Proteins
0.4882788
Cyclic Adenosine Monophosphate
0.45367825
Secondary Active Transport
0.42135817
Sodium Chloride
0.41488162
0.4882788
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Image of FIGURE 1
FIGURE 1

Sodium-coupled glucose absorption. This electrogenic transport process provides for the uphill transport of glucose across the apical membrane of villus epithelial cells in the small intestine by coupling glucose movement to that of sodium via SGLT1. Sodium movement is energized by the low intracellular sodium concentration established by the basolateral Na,K-ATPase. Glucose exits the basolateral membrane via the facilitated diffusion pathway, GLUT-2. Similar mechanisms exist for a variety of other nutrients, such as amino acids. Conjugated bile acids are also reabsorbed in the terminal ileum via a comparable transport mechanism.

Citation: Barrett K, Bertelsen L. 2003. Physiological Regulation of Gastrointestinal Ion Transport, p 241-266. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch14
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Image of FIGURE 2
FIGURE 2

Electrogenic sodium absorption. This transport mechanism is found in the colon, and provides sodium uptake via apical ENaC sodium channels in response to gradients established by the basolateral Na,K-ATPase. Basolateral potassium channels provide for potassium recycling as needed. Water and chloride ions are absorbed paracellularly to balance electrical and osmotic forces.

Citation: Barrett K, Bertelsen L. 2003. Physiological Regulation of Gastrointestinal Ion Transport, p 241-266. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch14
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Image of FIGURE 3
FIGURE 3

Electroneutral sodium chloride absorption. This process is expressed in both the small and large intestine and contributes to water absorption when nutrients are absent. Sodium and chloride are taken up across the apical membrane via the coupled activity of two exchangers. The identity of the chloride/bicarbonate exchanger involved in this process is still controversial, as is the involvement of a basolateral potassium/chloride cotransporter. The apical sodium/hydrogen exhanger, NHE3, can be negatively regulated by increases in cAMP. For additional details, see text.

Citation: Barrett K, Bertelsen L. 2003. Physiological Regulation of Gastrointestinal Ion Transport, p 241-266. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch14
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Image of FIGURE 4
FIGURE 4

Electrogenic chloride secretion. This transport mechanism occurs throughout the gastrointestinal tract and drives water and sodium secretion via the paracellular route. Chloride is taken up across the basolateral membrane via the sodium/potassium/chloride cotransporter, NKCC1, in response to the sodium concentration gradient established by the basolateral Na,K-ATPase. Potassium can be recycled by various channels for this cation on the basolateral membrane; one class of channels involved is regulated by calcium and appears to belong to the IK1 family, whereas the existence of cAMPregulated channels is still hypothetical at present. Chloride exits across the apical membrane predominantly via cAMP-regulated CFTR chloride channels, although there is emerging evidence for additional involvement of calcium-activated CLCA channels.

Citation: Barrett K, Bertelsen L. 2003. Physiological Regulation of Gastrointestinal Ion Transport, p 241-266. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch14
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Image of FIGURE 5
FIGURE 5

Electroneutral bicarbonate secretion. Bicarbonate is generated intracellularly via the action of carbonic anhydrase (not shown), or enters across the basolateral membrane via secondary active transport mediated by the sodium/bicarbonate cotransporter, and energized by the sodium gradient established by the Na,KATPase. In response to increases in cAMP, apical CFTR chloride channels allow the outflow of chloride across the apical membrane, which is in turn exchanged for intracellular bicarbonate, via an anion exchanger whose identity is still controversial, as shown. A housekeeping basolateral sodium/hydrogen exchanger (NHE-1) is involved in intracellular pH homeostasis during the process. For further details, see text.

Citation: Barrett K, Bertelsen L. 2003. Physiological Regulation of Gastrointestinal Ion Transport, p 241-266. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch14
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Image of FIGURE 6
FIGURE 6

Electrogenic bicarbonate secretion. The major features of this model are identical to the transport mechanism depicted in Fig. 5 , except that bicarbonate exits the cell across the apical membrane via a conductive pathway, which may be CFTR. For additional details, see text.

Citation: Barrett K, Bertelsen L. 2003. Physiological Regulation of Gastrointestinal Ion Transport, p 241-266. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch14
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Image of FIGURE 7
FIGURE 7

Electrogenic potassium secretion. This transport mechanism is expressed in the colon and contributes to whole-body potassium homeostasis. Potassium is taken up across the basolateral membrane by the NKCC1 cotransporter in response to the sodium gradient established by the Na,KATPase. Potassium then exits the cell across apical potassium channels that have not yet been identified at the molecular level. Water and chloride follow paracellularly to maintain osmotic and electrical balance between compartments.

Citation: Barrett K, Bertelsen L. 2003. Physiological Regulation of Gastrointestinal Ion Transport, p 241-266. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch14
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Image of FIGURE 8
FIGURE 8

Intercellular regulation of gastrointestinal transport. Enteric nerves release neurotransmitters and peptides, which interact largely with the epithelial cells themselves to alter transport. Regulatory peptides from endocrine cells are released both apically and basolaterally, and local diffusion of these peptides to nearby epithelial cells (paracrine regulation) can regulate ion transport. Blood-borne peptides from distant endocrine cells can also induce regulatory actions in a similar fashion. Finally, resident or infiltrating immune/inflammatory cells can be stimulated to release mediators, which in turn act on the epithelium. There is also substantial evidence for cross talk among these various regulatory mechanisms (not shown). For further details, see text.

Citation: Barrett K, Bertelsen L. 2003. Physiological Regulation of Gastrointestinal Ion Transport, p 241-266. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch14
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Image of FIGURE 9
FIGURE 9

The regulatory action of CFTR on other ion channels and transporters. In addition to its role as a chloride channel, CFTR exerts modulatory influences over a variety of other transport proteins and processes as shown. These include inhibition of the epithelial Na channel, ENaC, induction of increased expression of NKCC1, and activation of basolateral Kchannels.

Citation: Barrett K, Bertelsen L. 2003. Physiological Regulation of Gastrointestinal Ion Transport, p 241-266. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch14
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Image of FIGURE 10
FIGURE 10

Pathways for the stimulation and inhibition of Ca-dependent chloride secretory responses. Agonists that evoke increases in intracellular Ca (here exemplified by the muscarinic agonist, CCh, binding to an M3-muscarinic receptor) are capable of inducing CaMK-stimulated chloride secretory responses via activation of calciumactivated chloride channel (CLCA). At the same time, increases in intracellular Ca will transactivate the EGF receptor and subsequently recruit the ERK1/2 isoforms of MAPK, which by as yet unknown mechanisms reduces the secretory responses. In a divergent mechanism, activation of EGFr by EGF itself results in stimulation of PI 3-K, which inhibits but does not also stimulate chloride secretion. This action is mediated by inhibition of a basolateral potassium channel, reducing the driving force for apical chloride secretion. For further details, see text.

Citation: Barrett K, Bertelsen L. 2003. Physiological Regulation of Gastrointestinal Ion Transport, p 241-266. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch14
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Tables

Generic image for table
TABLE 1

Active transport mechanisms in the mammalian small intestine and colon

Citation: Barrett K, Bertelsen L. 2003. Physiological Regulation of Gastrointestinal Ion Transport, p 241-266. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch14
Generic image for table
TABLE 2

Carriers, pumps, and channels expressed in intestinal epithelial cells

Citation: Barrett K, Bertelsen L. 2003. Physiological Regulation of Gastrointestinal Ion Transport, p 241-266. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch14

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