CELLULAR MECHANISMS OF Cl- ABSORPTION AND SECRETION

Cl- absorption occurs throughout the small and large intestine and is often closely linked to Na+ absorption. Cl- and Na+ absorption may be coupled via either an electrical potential difference or by pHi. However, sometimes no coupling takes place, and the route of Cl- movement may be either paracellular or transcellular.
"Voltage-Dependent" Cl- Absorption Represents Coupling of Cl- Absorption to Electrogenic Na+ Absorption in Both the Small and the Large Intestine

Cl- absorption can be a purely passive process (Fig. 43-4A), driven by the electrochemical gradient for Cleither across the tight junctions (paracellular route) or across the individual membranes of the epithelial cell (transcellular route). In either case, the driving force for Cl - absorption derives from either of the two electrogenic mechanisms of Na+ absorption described previously-namely, nutrient-coupled transport in the small intestine and epithelial Na+ channels in the distal end of the colon. This process is referred to as "voltage-dependent Cl- absorption"; it is not an active transport process.

Figure 43-4 Modes of Cl- absorption by the intestine. A, In "voltage-dependent" Cl- absorption, Cl- may passively diffuse from lumen to blood across the tight junctions, driven by the lumen-negative transepithelial voltage (paracellular route). Alternatively, Cl - may diffuse through apical and basolateral Cl- channels. The thickness of the arrows in the inset indicates the relative magnitude of the Cl - -absorptive flux through this pathway. B, In the absence of a parallel Na-H exchanger, "electroneutral Cl-HCO3 exchange" at the apical membrane results in Cl - absorption and secretion. C, "Electroneutral NaCl" absorption (see Fig. 43-3C) can mediate Cl - absorption in the interdigestive period. Note that intracellular pH couples the two exchangers. CA, carbonic anhydrase.
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Within the small intestine, induction of a lumen-negative potential difference by glucose- and amino acid-induced Na+ absorption (see Fig. 43-3A) provides the driving force for Cl - absorption. As noted earlier, nutrient-coupled Na+ absorption primarily represents a villous cell process that occurs in the postprandial period and is insensitive to cyclic nucleotides and changes in [Ca+2]i. Voltage-dependent Cl- absorption shares these properties. It is uncertain whether the route of voltage-dependent Cl- absorption is transcellular or paracellular. In the large intestine, especially in the distal segment, electrogenic Na+ absorption via the ENaC Na+ channel (see Fig. 43-3D) also induces a lumen-negative potential difference that provides the driving force for colonic voltage-dependent Cl- absorption. Factors that increase or decrease the voltage difference will similarly affect Cl - absorption.
Electroneutral Cl-HCO3 Exchange Results in Cl- Absorption and Secretion in the Ileum and Colon

Electroneutral Cl-HCO3 exchange, in the absence of parallel Na-H exchange, occurs in villous cells in the ileum and in surface epithelial cells in the large intestine (see Fig. 43-4B). It is not known whether this process occurs in the cells lining the crypts. A Cl-HCO3 exchanger in the apical membrane is responsible for the 1:1 exchange of apical Cl- for intracellular . In humans, this Cl-HCO3 exchanger is DRA (p. 69). The details of Cl- movement across the basolateral membrane are not well understood, but may involve the ClC-2 Cl- channel (p. 169).
CONGENITAL CHLORIDORRHEA

The congenital absence of an apical Cl-HCO3 exchanger (which mediates the Cl-HCO3 involved in electroneutral NaCl absorption) is an autosomal recessive disorder known as congenital chloridorrhea or congenital chloride diarrhea (CLD). Affected children have diarrhea with an extremely high stool [Cl-], a direct consequence of absence of the apical membrane Cl-HCO3 exchanger. In addition, because secretion is reduced, patients are alkalotic (i.e., have an increased plasma ). The gene for congenital chloridorrhea is located on chromosome 7q31. The gene product is the same as that of the downregulated-in-adenoma (DRA) gene. DRA (also known as SLC26A3) is a member of the SAT (sulfate anion transporter) family of sulfate transporters (p. 69) and mediates Cl-HCO3 exchange. In addition, DRA transports sulfate and other anions. However, DRA is distinct from the AE (anion exchanger) gene family that encodes the Cl-HCO3 exchangers in erythrocytes and several other tissues. Indeed, Cl-HCO3 exchange in the renal tubule, erythrocytes, and other cells is unaffected in individuals with CLD, as are other intestinal transport processes.
Parallel Na-H and Cl-HCO3 Exchange in the Ileum and the Proximal Part of the Colon Mediates Cl Absorption During the Interdigestive Period

"Electroneutral NaCl absorption," discussed in connection with Na+ absorption (see Fig. 43-3C), also mediates Cl- absorption in the ileum and proximal part of the colon (see Fig. 43-4C). The apical step of Clabsorption by this mechanism is mediated by parallel Na-H and Cl-HCO3 exchanges, which are coupled via pHi.
Electrogenic Cl- Secretion Occurs in Crypts of Both the Small and the Large Intestine

In the previous three sections, we saw that intestinal Cl- absorption occurs via three mechanisms. The small intestine and the large intestine are also capable of active Cl- secretion, although Cl- secretion is believed to occur mainly in the crypts rather than in either the villi or surface cells. Spatial Distribution of Cl- Secretion A small amount of Cl- secretion probably occurs in the "basal" state but is masked by the higher rate of the three Cl- absorptive processes that are discussed earlier in this subchapter. However, Cl- secretion is markedly stimulated by secretagogues such as acetylcholine and other neurotransmitters. Moreover, Clsecretion is the major component of the ion transport events that occur during most clinical and experimental diarrheal disorders. The cellular model of active Cl- secretion is outlined in Figure 43-5 and includes three transport pathways on the basolateral membrane: (1) an Na-K pump, (2) an Na/K/Cl cotransporter, and (3) two types of K+ channels. In addition, a Cl- channel is present on the apical membrane. This complex Cl- secretory system is energized by the Na-K pump, which generates a low [Na+]i and provides the driving force for Cl- entry across the basolateral membrane via Na/K/Cl cotransport. As a result, [Cl-]i is raised sufficiently that the Cl electrochemical gradient favors the passive efflux of Cl - across the apical membrane. One consequence of these many transport processes is that the transepithelial voltage becomes more lumen-negative, thereby promoting voltage-dependent Na+ secretion. This Na+ secretion that accompanies active Cl- secretion presumably occurs through the tight junctions (paracellular pathway). Thus, the net result is stimulation of NaCl and fluid secretion. Normally-that is, in the unstimulated state-the crypts secrete little Cl- because the apical membrane Clchannels are either closed or not present. Cl- secretion requires activation by cyclic nucleotides or [Ca2+], which are increased by any of several secretagogues, including (1) bacterial exotoxins (i.e., "enterotoxins"), (2) hormones and neurotransmitters, (3) products of cells of the immune system (e.g., histamine), and (4) laxatives (see Table 43-3).
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Figure 43-5 Cellular mechanism of electrogenic Cl - secretion by crypt cells. The basolateral Na/K/Cl cotransporter brings Cl - into the crypt cell; the Cl- exits across the apical Cl - channel. Secretagogues may open pre-existing Cl- channels or cause subapical vesicles to fuse with the apical membrane, thus delivering new Cl- channels. The paracellular pathway allows Na+ movement from blood to lumen, driven by the lumen-negative transepithelial voltage. The thickness of the arrows in the inset indicates that the magnitude of the Cl - -secretory flux through this pathway is the same throughout the intestine. ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate.

Some secretagogues initially bind to membrane receptors and stimulate the activation of adenylyl cyclase (vasoactive intestinal peptide [VIP]), guanylyl cyclase (the heat-stable toxin of E. coli), or phospholipase C (acetylcholine). Others increase [Ca2+]i by opening Ca2+ channels at the basolateral membrane. The resulting activation of one or more protein kinases-by any of the aforementioned pathways-increases the Clconductance of the apical membrane either by activating pre-existing Cl- channels or by inserting into the apical membrane Cl- channels that-in the unstimulated state-are stored in subapical membrane vesicles. In either case, Cl- is now able to exit the cell through apical Cl- channels. The resulting decrease in [Cl-]i leads to increased uptake of Na+, Cl-, and K+ across the basolateral membrane via the Na/K/Cl cotransporter. The Na+ is recycled out of the cell via the Na-K pump. The K+ is recycled via basolateral K+ channels that are opened by the same protein kinases that increase Cl- conductance. The net result of all these changes is the initiation of active Cl- secretion across the epithelial cell. The induction of apical membrane Cl- channels is extremely important in the pathophysiology of many diarrheal disorders. The box Secretory Diarrhea at the end of this chapter discusses the changes in ion transport that occur in secretory diarrheas such as cholera. A central role in cystic fibrosis has been posited for the cystic fibrosis transmembrane regulator (CFTR) Cl- channel in the apical membrane (p. 916). However, more than one (and possibly several) Cl- channels are present in the intestine, and CFTR may not be the only Cl- channel associated with active Cl- secretion.
Printed from STUDENT CONSULT: Medical Physiology (on 24 August 2006) 2006 Elsevier