The colonic epithelium has both absorptive and secretory functions. The transport is characterized by a net absorption of NaCl, short-chain fatty acids (SCFA), and water, allowing extrusion of a fe...

Electrolyte Transport in the Mammalian Colon: Mechanisms and Implications for Disease

Calcium-activated chloride channels (CaCCs) play important roles in cellular physiology, including epithelial secretion of electrolytes and water, sensory transduction, regulation of neuronal and cardiac excitability, and regulation of vascular tone. This review discusses the physiological roles of these channels, their mechanisms of regulation and activation, and the mechanisms of anion selectivity and conduction. Despite the fact that CaCCs are so broadly expressed in cells and play such important functions, understanding these channels has been limited by the absence of specific blockers and the fact that the molecular identities of CaCCs remains in question. Recent status of the pharmacology and molecular identification of CaCCs is evaluated.

Calcium-activated chloride channels

Cystic fibrosis (CF) is a fatal genetic disease caused by abnormalities in fluid and electrolyte transport in exocrine epithelia. Both absorptive and secretory processes are affected by an underlying membrane defect in Cl- permeability. However, the impact of the defect on transport function is tissue specific. Net electrolyte absorption is decreased in the sweat duct, increased in airway epithelia, and not affected in intestine. The defect is expressed in secretion as a consistent failure in most, if not all, exocrine tissues, to beta-adrenergically stimulated and cAMP mediated secretory response. However, the secretory response to cholinergic and Ca2(+)-mediated stimulation is normal in the sweat gland, apparently normal in the airway, but absent in the intestine. The basic defect is not fatal in and of itself, and the imbalance between absorption and secretory functions may be of some selective advantage to heterozygotes in surviving complications of intestinal infections. The inherent defect in transport is probably the primary physiological cause of the ultimately fatal secondary infections in the lungs of CF homozygotes.

Cystic fibrosis: a disease in electrolyte transport.

Chloride secretion is the major determinant of mucosal hydration throughout the gastrointestinal tract, and chloride transport is also pivotal in the regulation of fluid secretion by organs that drain into the intestine. Moreover, there are pathological consequences if chloride secretion is either reduced or increased such as in cystic fibrosis and secretory diarrhea, respectively. With the molecular cloning of many of the proteins and regulatory factors that make up the chloride secretory mechanism, there have been significant advances in our understanding of this process at the cellular level. Similarly, emerging data have clarified the intercellular relationships that govern the extent of chloride secretion. The goal of our article is to review this area of investigation, with an emphasis on recent developments and their implications for the physiology and pathophysiology of chloride transport.

Chloride secretion by the intestinal epithelium: molecular basis and regulatory aspects.

Grubb, Barbara R., and Richard C. Boucher. Pathophysiology of Gene-Targeted Mouse Models for Cystic Fibrosis. Physiol. Rev. 79, Suppl.: S193–S214, 1999. — Mutations in the gene causing the fatal di...

Pathophysiology of Gene-Targeted Mouse Models for Cystic Fibrosis

Sodium ion and chloride transport was studied in vitro in small intestinal and colonic tissue from patients with cystic fibrosis (CF) and from non-CF control subjects matched as to age and sex Normal histological appearance and substantial response to mucosal glucose (5 mM, ileum) or mucosal amiloride (10(-5) M, colon) indicated normal tissue viability in both control and CF tissues Electroneutral NaCl absorption was demonstrated in the small intestine of control subjects and CF patients Small intestinal and colonic tissues of control subjects responded to four secretagogues (theophylline, 5 mM; prostaglandin E2, 10(-6) M; calcium ionophore (A23187), 10(-5) M; bethanechol, 5 x 10(-5) M), with electrogenic chloride secretion The tissues of CF patients, however, did not respond to any of the test secretagogues These studies demonstrate that an abnormality in chloride transport is present in the small intestinal and colonic epithelia of CF patients Unlike airway epithelia, which secrete chloride in response to Ca ionophore, the intestinal epithelia of CF patients do not respond to either cAMP- or Ca-mediated secretagogues This abnormality in intestinal electrolyte transport may play a role in the pathogenesis of meconium impactions in CF patients

R G Azizkhan

Papers

Altered intestinal chloride transport in cystic fibrosis.