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Supramaximal cholecystokinin displaces Munc18c from the pancreatic acinar basal surface, redirecting apical exocytosis to the basal membrane
Herbert Y. Gaisano, … , William S. Trimble, Anne Marie F. Salapatek
Herbert Y. Gaisano, … , William S. Trimble, Anne Marie F. Salapatek
Published December 1, 2001
Citation Information: J Clin Invest. 2001;108(11):1597-1611. https://doi.org/10.1172/JCI9110.
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Article

Supramaximal cholecystokinin displaces Munc18c from the pancreatic acinar basal surface, redirecting apical exocytosis to the basal membrane

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Abstract

Exocytosis at the apical surface of pancreatic acinar cells occurs in the presence of physiological concentrations of cholecystokinin (CCK) but is inhibited at high concentrations. Here we show that Munc18c is localized predominantly to the basal membranes of acinar cells. Supramaximal but not submaximal CCK stimulation caused Munc18c to dissociate from the plasma membrane, and this displacement was blocked by protein kinase C (PKC) inhibitors. Conversely, whereas the CCK analog CCK-OPE alone failed to displace Munc18c from the membrane, this agent caused Munc18c displacement following minimal PKC activation. To determine the physiological significance of this displacement, we used the fluorescent dye FM1-43 to visualize individual exocytosis events in real-time from rat acinar cells in culture. We showed that supramaximal CCK inhibition of secretion resulted from impaired apical secretion and a redirection of exocytic events to restricted basal membrane sites. In contrast, CCK-OPE evoked apical exocytosis and could only induce basolateral exocytosis following activation of PKC. Infusion of supraphysiological concentrations of CCK in rats, a treatment that induced tissue changes reminiscent of mild acute pancreatitis, likewise resulted in rapid displacement of Munc18c from the basal membrane in vivo.

Authors

Herbert Y. Gaisano, Manfred P. Lutz, Juergen Leser, Laura Sheu, Grit Lynch, Lan Tang, Yoshikazu Tamori, William S. Trimble, Anne Marie F. Salapatek

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Figure 4

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Fluorescence microscopy of 1 μM CCK-OPE–stimulated apical exocytosis. (a...
Fluorescence microscopy of 1 μM CCK-OPE–stimulated apical exocytosis. (a) A 3D-reconstructed image of 0.6-μm confocal cuts of the full thickness of a FM1-43–labeled triplet acinus stimulated by 1 μM CCK-OPE for 5 minutes (right). The phase contrast image is also shown (left). (b) Epifluorescence FM1-43 staining of another triplet acinus similarly stimulated with 1 μM CCK-OPE. Shown are the phase contrast image (left), basal fluorescent levels (middle), and the fluorescent image after 1 minute of stimulation (right). (c) The same acinus as in b where images were acquired at 1 frame per second. Regions of interest were drawn as indicated and graphed to show the kinetics of fluorescent changes in real time at these regions — the ZG pole, the apex, and a representative basal plasma membrane region. (d) A graphical analysis of these fluorescent changes (16 cells from doublets to four-cell acini from four experiments) obtained at peak levels. (e–j) The washout of FM1-43 fluorescence from an acinus stimulated with 1 μM CCK-OPE to show that the fusion pores of ZGs that have undergone exocytotic fusion remained open. (e) A phase contrast of the acinus. (f) Epifluorescent microscopy of FM1-43 fluorescence of this acinus stimulated by 1 μM CCK-OPE for 5 minutes. This acinus was then subjected to four washes (g–j) with FM1-43–free media. Note that with each wash, the FM1-43 fluorescence progressively diminished from the innermost portions of the ZG poles of the acinus toward the apical lumen (first [g] to third [i] washes), and finally the apical lumenal fluorescence was washed off (fourth wash [j]). Bar = 20 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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