Cellular basis of diarrhoea. The Croonian lecture 1989

A wide range of different stimuli is perceived by the intestinal epithelium. They include luminal factors, especially bacterial toxins, and agonists such as inflammatory mediators and neuro peptides, acting from the interstitial fluid surrounding the epithelial cells. It is likely that in any individual patient with diarrhoea there is a range of stimuli acting upon the epithelium. Specific receptors on the apical and basolateral membrane, activated by these stimuli, transduce the perceived signals to stimulate a series of membrane-bound enzyme systems. They in turn generate second messengers which are liberated into the cytoplasm. These include cyclic adenosine monophosphate, cyclic guanosine monophosphate, inositol triphosphate (which goes on to liberate free calcium), and diacyl glycerol. Each of these second messengers activates a different protein kinase, each of which then induces the phosphorylation of a series of cytoplasmic and membrane-bound proteins. Each of the protein kinases is likely to influence the activity of the others so that their effects are closely integrated. The final common pathways through which intestinal secretory stimuli pass involve the opening of an anion channel in the apical membrane, together with the stimulated uptake of chloride at the basolateral membrane. Anions, especially chloride and possibly bicarbonate, are then secreted into the lumen, and sodium and water passing between the cells accompany them. The net result is secretion of salt and water, which lies at the centre of a number of diarrhoeal diseases.