title: Defective regulation of apical membrane chloride transport and exocytosis in cystic fibrosis.
abstract: A biochemical link is proposed between recent observations on defective regulation of Cl- transport in CF respiratory epithelial cells and studies showing altered biological activity of calmodulin in exocrine glands from CF patients. A consensus is emerging that defective beta-adrenergic secretory responsiveness in CF cells is caused by a defect in a regulator protein at a site distal to cyclic AMP formation. Our results indicate that this protein might be a specific calmodulin acceptor protein which modifies the activity of calmodulin in epithelial cells. Alteration in Ca2+/calmodulin dependent regulation of Cl- transport and protein secretion could explain (i) alterations in Ca2+ homeostasis seen in CF, (ii) defective beta-adrenergic responses of CF cells, and (iii) the observed inability of cyclic AMP (acting via its specific protein kinase, A-kinase) to open apical membrane Cl- channels in CF epithelial cells. Most of the physiological abnormalities of CF including elevated sweat electrolytes and hyperviscous mucus can be explained on this basis.
authors: Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff, U.K.
authors: M A
authors: MA
authors: McPherson
authors: D K
authors: DK
authors: Shori
authors: R L
authors: RL
authors: Dormer
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism / Q000503:physiopathology*; D005088:Exocrine Glands / Q000378:metabolism; D005089:Exocytosis; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D008954:Models, Biological; D011943:Receptors, Adrenergic, beta / Q000502:physiology
chemical_list: D002147:Calmodulin; D002712:Chlorides; D007473:Ion Channels; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D002118:Calcium