Medical Physiology, 3rd Edition

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 through 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 intestine and the large intestine

Cl absorption can be a purely passive process (Fig. 44-4A), driven by the electrochemical gradient for Cl either 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: nutrient-coupled transport (see pp. 903–904) in the small intestine and ENaC channels in the distal end of the colon (see p. 905). This process is referred to as voltage-dependent Cl absorption; it is not an active transport process.

image

FIGURE 44-4 Modes of Cl absorption by the intestine. A, In voltage-dependent Cl absorption, Cl may passively diffuse from lumen to blood across tight junctions, driven by a lumen-negative transepithelial voltage (paracellular route). Alternatively, Cl may diffuse through apical and basolateral Cl channels. B, In the absence of a parallel Na-H exchanger, electrogenic Cl-HCO3 exchange at the apical membrane results in Cl absorption and image secretion. C, Electroneutral NaCl absorption (see Fig. 44-3C) can mediate Cl absorption in the interdigestive period. Intracellular pH may couple the two exchangers. The thickness of the arrows in the insets indicates the relative magnitudes of Cl absorptive fluxes in different segments. CA, carbonic anhydrase.

Within the small intestine, induction of a lumen-negative potential difference by glucose- and amino acid–induced Na+ absorption (see Fig. 44-3A) provides the driving force for Cl absorption that occurs following a meal. As noted above, 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 [Ca2+]i. Voltage-dependent Cl absorption shares these properties. It is most likely that the route of voltage-dependent Cl absorption is paracellular.

In the large intestine, especially in the distal segment, electrogenic Na+ absorption via ENaC channels (see Fig. 44-3D) 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 similarly affect Cl absorption (Box 44-2).

Box 44-2

Congenital Chloridorrhea

The congenital absence of an apical Cl-HCO3 exchanger (which mediates the Cl-HCO3 exchange involved in electroneutral NaCl absorption) is an autosomal recessive disorder known as congenital chloridorrhea or congenital Cl diarrhea (CLD). Affected children have diarrhea with an extremely high stool [Cl], a direct consequence of the absence of the apical membrane Cl-HCO3 exchanger. In addition, because image secretion is reduced, patients are alkalotic (i.e., have an increased plasma [image]). The gene for congenital chloridorrhea is located on chromosome band 7q31. The gene product is the same as that of the DRA gene. DRA (SLC26A3; see Table 5-4) mediates electrogenic Cl-HCO3 exchange. In addition, DRA transports sulfate and other anions. However, DRA is distinct from other electrogenic Cl-HCO3 exchangers in the duodenum and pancreatic ducts (SLC26A6) as well as the anion exchanger (AE) subfamily that encodes electroneutral Cl-HCO3 exchangers in erythrocytes and several other tissues. Indeed, Cl-HCO3 exchange in these other tissues is unaffected in individuals with CLD, as are other intestinal transport processes.

Electroneutral Cl-HCO3 exchange results in Cl absorption and image 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. 44-4B). 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 image. In humans, this Cl-HCO3 exchanger is DRA (see Table 5-4). The details of Cl movement across the basolateral membrane are not well understood, but the process may involve a ClC-2 Cl channel (see Table 6-2, family No. 16).

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. 44-3C), also mediates Cl absorption in the ileum and proximal part of the colon (see Fig. 44-4C). The apical step of Clabsorption by this mechanism is mediated by parallel Na-H exchange (NHE3 or SLC9A3) and Cl-HCO3 exchange (DRA or SLC26A3), which are coupled through 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. imageN44-4

N44-4

Spatial Distribution of Cl Secretion

Contributed by Emile Boulpaep, Walter Boron

We have already introduced the concept of a spatial distribution of absorptive and secretory processes in which secretory processes are restricted to crypt epithelial cells and absorptive processes to villous/surface epithelial cells in both the small and large intestine (see pp. 901–902). However, this model is an oversimplification. For example, active Cl secretion occurs in villous/surface epithelial cells as well as in crypt epithelial cells.

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 above in this subchapter. However, Cl secretion is markedly stimulated by secretagogues such as acetylcholine and other neurotransmitters. Moreover, Cl secretion is the major component of the ion transport events that occur during many clinical and experimental diarrheal disorders.

The cellular model of active Cl secretion is outlined in Figure 44-5 and includes three transport pathways on the basolateral membrane: (1) an Na-K pump, (2) an Na/K/Cl cotransporter (NKCC1 or SLC12A2), and (3) two types of K+ channels (IK1 and BK). In addition, a Cl channel (cystic fibrosis transmembrane conductance regulator [CFTR]) 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 through 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, which promotes 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.

image

FIGURE 44-5 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 the relative magnitudes of Cl secretory fluxes in different segments.

Normally (i.e., in the unstimulated state) the crypts secrete little Cl because the apical membrane Cl channels are either closed or not present. Cl secretion requires stimulation 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 (Table 44-2). These secretagogues act by increasing intracellular levels of cyclic nucleotides or Ca2+. For example, vasoactive intestinal peptide (VIP) acts through adenylyl cyclase; the heat-stable toxin of E. coli acts through guanylyl cyclase; and acetylcholine acts through phospholipase C.

TABLE 44-2

Mode of Action of Secretagogues

CATEGORY

SECRETAGOGUE

SECOND MESSENGER

Bacterial enterotoxins

Cholera toxin

cAMP

Escherichia coli toxins: heat labile

cAMP

E. coli toxins: heat stable

cGMP

Yersinia toxin

cGMP

Clostridium difficile toxin

Ca2+

Hormones and neurotransmitters

VIP

cAMP

Guanylin

cGMP

Acetylcholine

Ca2+

Bradykinin

Ca2+

Serotonin (5-HT)

Ca2+

Immune cell products

Histamine

cAMP

Prostaglandins

cAMP

Laxatives

Bile acids

Ca2+

Ricinoleic acid

?

The resulting activation of one or more protein kinases—by any of the aforementioned pathways—increases the Cl conductance 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 now exits the cell through apical Cl channels; the result is a decrease in [Cl]i, which leads to increased uptake of Na+, Cl, and K+ across the basolateral membrane via NKCC1. The Na+ recycles out of the cell via the Na-K pump. The K+ recycles through basolateral K+channels that open in response to 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. Box 44-3 discusses the changes in ion transport that occur in secretory diarrheas such as that associated with cholera. A central role in cystic fibrosis has been posited for the CFTR Cl channel in the apical membrane (see p. 122). However, other Cl channels, including the Ca2+-activated CaCC (see Table 6-2, family No. 17) are likely present in the intestine and may contribute to active Cl secretion.

Box 44-3

Secretory Diarrhea

Diarrhea is a common medical problem and can be defined as a “symptom” (i.e., an increase in the number of bowel movements or a decrease in stool consistency) or as a sign (i.e., an increase in stool volume of >0.2 L/24 hr). Diarrhea has many causes and can be classified in various ways. One classification divides diarrheas by the causative factor. The causative factor can be failure to absorb a dietary nutrient, in which case the result is an osmotic diarrhea. An example of osmotic diarrhea is that caused by primary lactase deficiency. Alternatively, the causative factor may not be lack of absorption of a dietary nutrient, but rather endogenous secretion of fluid and electrolytes from the intestine, in which case the result is secretory diarrhea.

The leading causes of secretory diarrhea include infections with E. coli (the major cause of traveler's diarrhea) and cholera (a cause of substantial morbidity and mortality in developing countries). In these and other infectious diarrheas, an enterotoxin produced by one of many bacterial organisms raises intracellular concentrations of cAMP, cGMP, or Ca2+ (see Table 44-2).

A second group of secretory diarrheas includes those produced by different, relatively uncommon hormone-producing tumors. Examples of such tumors include those that produce VIP (Verner-Morrison syndrome), glucagon (glucagonomas), and serotonin (carcinoid syndrome). These secretagogues act by raising either [cAMP]i or [Ca2+]i (see Table 44-2). When tumors produce these secretagogues in abundance, the resulting diarrhea can be copious and explosive.

As we have seen, the secretory diarrheas have in common their ability to increase [cAMP]i, [cGMP]i, or [Ca2+]iTable 44-4 summarizes the mechanisms by which these second messengers produce the secretory diarrhea. Because the second messengers do not alter the function of nutrient-coupled Na+ absorption, administration of an oral rehydration solution containing glucose and Na+ is effective in the treatment of enterotoxin-mediated diarrhea (see Box 44-1).

 

SMALL INTESTINE

LARGE INTESTINE

Length (m)

6

2.4

Area of apical plasma membrane (m2)

~200

~25

Folds

Yes

Yes

Villi

Yes

No

Crypts or glands

Yes

Yes

Microvilli

Yes

Yes

Nutrient absorption

Yes

No

Active Na+ absorption

Yes

Yes

Active K+ secretion

No

Yes