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 pH_i. However, sometimes no coupling takes place, and the route of Cl⁻ movement may be either paracellular or transcellular.

Voltage-dependent Cl – absorption

Cl⁻ absorption can be a purely passive process, 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 (namely, nutrient-coupled transport in the small intestine and the ENaCs in the distal end of the colon). This process is referred to as voltage-dependent Cl⁻ absorption; it is not an active transport process

Within the small intestine, induction of a lumen-negative potential difference by glucose and amino acid–induced Na⁺ absorption provides the driving force for Cl⁻ absorption that occurs following a meal. 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 through the ENaCs 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.

Electroneutral Cl-HCO3 exchange

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. 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 HCO₃⁻. In humans, this Cl-HCO₃ exchanger is DRA. The details of Cl⁻ movement across the basolateral membrane are not well understood, but the process may involve a ClC-2 Cl⁻ channel

Parallel Na-H and Cl-HCO3 exchange

The apical step of Cl⁻ absorption by this mechanism is mediated by parallel Na-H exchange (NHE3 or SLC9A3) and Cl-HCO₃ exchange (DRA or SLC26A3), which are coupled through pH_i

Electrogenic Cl− secretion

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. 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 most clinical and experimental diarrheal disorders. The cellular model of active Cl⁻ secretion is 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 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, 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 (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 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.

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 Cl⁻ conductance of the apical membrane either by activating preexisting 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 through the Na/K/Cl cotransporter (NKCC1). The Na⁺ is recycled out of the cell through the Na-K pump. The K⁺ is recycled through 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 titled Secretory Diarrhea 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 CFTR Cl⁻ channel in the apical membrane. 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.