cyclic-gmp and phenothiazine

The physiology of intestinal electrolyte transport is currently an area of intense research interest. Also, reports regularly appear that define possible roles of various endocrine, paracrine, and neurohumoral substances in regulating intestinal ion and water flux. A vast body of knowledge has appeared recently that focuses on the action of specific intracellular mediators or second messengers and certain biochemical events that are thought to be involved in this transport process. This area of research has drawn the attention of the clinical investigator as well as the basic scientist because of the implications of these findings to the understanding of secretory disorders of the gastrointestinal tract, in particular diarrheal disease. The purpose of this review is to focus on recent findings reported in three major areas: the physiology of intestinal electrolyte transport and its regulation; the pathophysiology of secretory diarrhea; and current thoughts and practices in the therapeutic approach to the disease.

Topics: Acid-Base Equilibrium; Adrenergic alpha-Agonists; Animals; Arachidonic Acids; Carbachol; Chlorides; Cholera Toxin; Cyclic AMP; Cyclic GMP; Diarrhea; Electric Stimulation; Electrolytes; Hydroxyeicosatetraenoic Acids; Intestinal Absorption; Intestinal Mucosa; Intestine, Small; Leukotrienes; Models, Biological; Narcotics; Phenothiazines; Phorbol 12,13-Dibutyrate; Phorbol Esters; Phosphorylation; Protein Kinase C; Receptors, Cholinergic; Receptors, Muscarinic; Renin-Angiotensin System; Sodium; Sodium-Potassium-Exchanging ATPase; Tetradecanoylphorbol Acetate

We report the regulation of cGMP accumulation induced by the heat-stable enterotoxin, STh, in the T84 human colonic cell line. STh binding to its receptor, guanylyl cyclase C (GCC), leads to elevated intracellular levels of cGMP. Prolonged exposure of T84 cells to STh induced refractoriness to further cGMP accumulation, without significant receptor internalization, but with reduced STh-induced cGMP synthesis by the receptor. Significantly, increased degradation of cGMP by a cGMP-specific phosphodiesterase was observed in desensitized cells. This is the first report on the desensitization of GCC, as well as the role of the Type V phosphodiesterase in inducing cellular refractoriness.

Topics: 1-Methyl-3-isobutylxanthine; 3',5'-Cyclic-GMP Phosphodiesterases; 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Bacterial Toxins; Cell Line; Cell Membrane; Cyclic GMP; Enterotoxins; Escherichia coli Proteins; Guanylate Cyclase; Humans; Kinetics; Milrinone; Phenothiazines; Purinones; Pyridones