Functional partitioning of epithelial protein kinase CaMKII in signal transduction.
The examination of the physiological role of CaMKII has made substantial progress in non-epithelial systems but little is known about its function in secretory epithelial cells. A prototypic exocrine cell, the acid secreting gastric parietal cell, largely redistributes its cytoplasmic tubulocisternal membranes (TC) to the secretory apical membrane (SA) after stimulation. We here present a dependence of physiological response on partitioned initial CaMKII activities redistributed between TC and SA. Initial acid secretion after cholinergic stimulation has doubled if activities of phosphatases PP1/PP2A and protein kinase PKC-alpha were inhibited by the inhibitors calyculin A and Gö 6976. CaMKII appears to be integrated in multienzyme complexes each specific for TC and SA. Therein, PP1/PP2A and PKC-alpha were found to permanently counteract initial CaMKII activities in different modes of transregulation. Remarkably, a dys-transregulated, hyperactive CaMKII at TC did not result in an increased acid secretion to the same extent. A simple mathematical model to estimate the share of TC- and SA-associated CaMKII activities in cholinergically induced acid secretion suggests that TC-associated CaMKII appears to autoregulate its contribution to the physiological response by a negative feedback control. Subcellular distribution and stimulus-dependent redistribution of domain-associated CaMKII signalosomes indicate a fine balanced, adaptive system to guarantee a stable physiological response.
Fährmann
Michael
M
Medizinische Hochschule Hannover, Abt. Gastroenterologie, Hepatalogie und Endokrinologie, c/o Institut für Pharmakologie, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. faehrmann.michael@mh-hannover.de
Kaufhold
Marc-André
MA
D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D004847:Epithelial Cells / Q000201:enzymology*; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D008962:Models, Theoretical; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011485:Protein Binding; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors; D021381:Protein Transport; D011817:Rabbits; D015398:Signal Transduction; D013347:Subcellular Fractions
D000632:Aminopyrine; D002217:Carbachol; D051571:Protein Kinase C-alpha; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases