Intestinal electrolyte secretion. History of a paradigm

The contemporary paradigm for active chloride secretion by vertebrate epithelial cells evolved, at least in part, from experiments that began in the laboratory of Dr William Silen at Beth Israel Hospital in Boston, Mass. It was first shown there that cyclic adenosine monophosphate and cholera toxin stimulate active chloride secretion when added to intestinal mucosa in vitro. The paradigm, which evolved further from experiments on shark rectal gland and flounder intestine at the Mt Desert Island Biological Laboratory in Salsbury Cove, Maine, is as follows: Chloride enters some epithelial cells by sodium-potassium-chloride cotransport with a stoichiometry of 1:1:2 and accumulates intracellularly because of the sodium gradient maintained by sodium-potassium-adenosinetriphosphatase in the basolateral membrane; the chloride is then released from the cell through chloride channels in the membrane opposite that of the cotransporter. If the cotransporter is basolateral and the channel is apical, chloride is secreted; if it is the other way around, chloride is absorbed. In a number of secretory epithelial cells, cyclic adenosine monophosphate activates these channels, thereby initiating secretion. A defect in the activation of these channels by cyclic adenosine monophosphate is the root cause of cystic fibrosis.