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Volume 272, Number 25, Issue of June 20, 1997 pp. 16056-16061
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Heterotrimeric G-protein G_q/11 Localized on Pancreatic Zymogen Granules Is Involved in Calcium-regulated Amylase Secretion

(Received for publication, December 23 1996, and in revised form, April 18, 1997)

Hirohide Ohnishi , Stephen A. Ernst ^§ , David I. Yule , Christopher W. Baker and John A. Williams

From the Departments of  Physiology, and ^§ Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109

The heterotrimeric G-protein G_q/11 was identified on pancreatic acinar zymogen granules and its function in calcium-regulated exocytosis was examined. Western blotting showed _q/11, but not _s or _o, to be localized to the zymogen granule membrane along with G-protein -subunit; all three  subunits were present in a plasma membrane fraction and the _q/11 signal was 30-fold more enriched in the plasma membrane as compared with granule membrane. Neither CCK receptors nor  subunits of the sodium pump, both plasma membrane markers were present on granule membranes. Immunohistochemistry of pancreatic lobules showed that _q/11 localized to the zymogen granule-rich apical region of acinar cells together with a much stronger signal at the basolateral plasma membrane. When the substance-P-related peptide GPAnt-2a, an antagonist of G_q/11, was introduced into streptolysin-O permeabilized acini to bypass the plasma membrane, the amylase release induced by 10 µM free calcium was potentiated in a concentration-dependent manner. By contrast, another substance-P-related peptide, GPAnt-1, an antagonist of G_o and G_i, showed no effect on calcium-induced amylase release from permeabilized acini. GPAnt-2a peptide also exerted an inhibitory effect on the total GTPase activity of the purified zymogen granules and a larger inhibitory effect on the GTPase activity of the G_q/11 protein immunopurified from zymogen granules. GPAnt-1, however, did not inhibit GTPase activity of either zymogen granules or immunopurified G_q/11. These results suggest that GPAnt-2a peptide augmented calcium-induced amylase release from permeabilized acini by inhibiting GTPase activity of the G_q/11 protein on zymogen granules. We conclude that G_q/11 protein on zymogen granules plays a tonic inhibitory role in calcium-regulated amylase secretion from pancreatic acini.

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