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Cellular Regulation of Pancreatic Secretion

John A. Williams, Daniel B. Burnham, Seth R. Hootman

10.1002/cphy.cp060321

Source: Supplement 18: Handbook of Physiology, The Gastrointestinal System, Salivary, Gastric, Pancreatic, and Hepatobiliary Secretion

Originally published: 1989

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Receptors
1.1 Functional Characterization
1.2 Receptor Binding Characteristics
1.3 Molecular Characterization of Membrane Receptors
1.4 Regulation of Pancreatic Receptors
2 Intracellular Messengers
2.1 Calcium‐Mediated Secretagogues
2.2 Cyclic AMP‐Mediated Secretagogues
2.3 Other Possible Intracellular Messengers
3 Effectors
3.1 Intracellular Receptors for Calcium, Diacylglycerol, and Cyclic AMP
3.2 Protein Phosphorylation as an Effector System
3.3 Exocytosis
Figure 1. Figure 1.

Inhibition of 125I‐CCK‐33 binding by cholecystokinin (CCK) analogues. Pancreatic membrane particles were incubated with 25 pM 125I‐CCK for 120 min in the presence or absence of various CCK analogues. Nonsaturable binding was subtracted from total binding, and saturable binding was expressed as the percent of maximal saturable binding. d‐CCK‐8, unsulfated COOH‐terminal octa‐peptide of CCK; G‐17‐II, sulfated gastrin‐17; G‐17‐I, unsulfated gastrin‐17; CCK‐4, COOH‐terminal tetrapeptide of CCK.

From Steigerwalt and Williams 157
Figure 2. Figure 2.

Electron‐microscopic autoradiograph of rat acini incubated for 1 h with 125I‐CCK‐33 at 37°C. Circles, silver grains overlying 125I‐CCK molecules. Note grains both on basolateral membrane and intracellularly.
Figure 3. Figure 3.

Autoradiograms of somatostatin (A) and CCK (B) cross‐linked to their receptors in pancreatic plasma membranes. A: 125I‐Tyr1 somatostatin was incubated in the presence or absence of 1 μM cyclic somatostatin and then cross‐linked with 0.1 mM n‐hydroxysuccinimide azidobenzoate and exposure to UV light. B: 125I‐CCK‐33 was incubated with mouse pancreatic acini in presence or absence of 0.1 μM CCK‐8 and then cross‐linked with 0.1 mM disuccinimidyl suberate. In both A and B, membranes were treated with 50 mM dithiothreitol (DTT) where specified.

A from Sakamoto et al. 142; B from Sakamoto et al. 140
Figure 4. Figure 4.

Time dependence of decrease in specific [3H]N‐methyl‐scopolamine (NMS) binding to guinea pig pancreatic acini cultured with 0.1 mM carbachol (open circles) or in control media (filled circles). At each indicated time, acini were rinsed and incubated for 60 min with 0.5 nM 3H]NMS.

From Hootman et al. 63
Figure 5. Figure 5.

Effect of Ca2+ removal on basal and caerulein‐stimulated amylase release from mouse pancreatic acini. EGTA, ethylene glycol‐bis(β‐aminoethylether)‐N,N'‐tetraacetic acid.

From Williams 179
Figure 6. Figure 6.

Kinetics of initial changes in [Ca2+] of pancreatic acini measured with quin 2 after stimulation by carbachol. Acini were suspended in medium containing 1.28 mM Ca2+ (A) or in medium containing 0.1 mM EGTA and no added Ca2+ (B). Concentration of carbachol shown was added at the arrow.

From Ochs et al. 108
Figure 7. Figure 7.

Relationship between amount of amylase released from pancreatic acini and [Ca2+]i. Release of amylase and rise in [Ca2+]i of quin 2‐loaded pancreatic acini were measured after addition of various concentrations of either carbachol (–1 μM) or inomycin (–1 μM).

From Ochs et al. 108
Figure 8. Figure 8.

Effect of inositol 1,4,5‐trisphosphate (IP3) on intracellular Ca2+ stores of leaky acinar cells. Calcium in the medium was measured with an ion‐selective electrode. Initial upward trace, fall in medium Ca2+ as it is taken up by acinar organelles; abrupt downward deflection, Ca2+ release induced by IP3.

From Streb et al. 161
Figure 9. Figure 9.

Synergism of amylase release from mouse pancreatic acini induced by the calcium ionophore A23187 2 μM) and the phorbol ester 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) 10−6 M). Together the two are able to reproduce effect of maximal concentration of carbachol (CCh).
Figure 10. Figure 10.

Ability of secretin, vasoactive intestinal polypeptide (VIP), and peptide histidine isoleucine (PHI) to increase cAMP in dispersed acini from guinea pig pancreas.

From Jensen et al. 76
Figure 11. Figure 11.

Demonstration of separate calmodulin‐ and phospholipid‐dependent, Ca2+‐activated kinase activity in mouse pancreas cytosol. Acinar cytosol was initially treated with phenothiazine coupled to a solid matrix to remove endogenous calmodulin. Cytosol was incubated with [γ‐32P]ATP in the absence (‐) or presence (+) of Ca2+ alone (A), with added calmodulin (B), or added phosphatidylserine (C) and phosphorylated proteins resolved by polyacrylamide gel electrophoresis and autoradiography. Ca2+‐activated kinase activity is present in B and C and shown to act on different endogenous substrates.

From Burnham and Williams 18
Figure 12. Figure 12.

Autoradiographs of polyacrylamide gels of purified zymogen granules incubated with [32P]ATP and phosphatidylserine, in the presence (+) or absence (‐) of Ca2+. A: intact purified granules. B: granules extracted with KCl prior to 32P labeling. C: granules extracted with KCl after 32P labeling.

From Burnham et al. 16
Figure 13. Figure 13.

Ca2+ sensitivity of Ca2+‐activated protein phosphatase activity purified from pancreatic cytosol. [32P]casein was used as a substrate. Phosphatase activity is totally dependent on presence of calmodulin (CaM). TFP, trifluoperazine.

From Burnham 14
Figure 14. Figure 14.

Autoradiographs of soluble proteins obtained from mouse acini that were incubated with [32P]phosphate for 60 min and stimulated with 3 μM carbachol (CCh) for 5 min. Soluble proteins were subjected to 2‐dimensional poly‐acrylamide gel electrophoresis; proteins that undergo an alteration in phosphorylation in response to carbachol are numbered and indicated by arrows. IEF, isoelectric focusing dimension; SDS, sodium dodecyl sulfate.

[From Burnham et al. 15.]
Figure 15. Figure 15.

Schematic diagram of stimulus‐secretion coupling of pancreatic acinar cell protein secretion. ACh, acetylcholine; CAM, calmodulin; CCK, cholecystokinin; DAG, diacylglycerol; Gs, stimulatory guanine nucleotide‐binding protein; G?, unknown guanine nucleotide‐regulated protein; IP3, inositol 1,4,5‐trisphosphate; PIP2, phosphatidylinositol 4,5‐bisphosphate; PK, protein kinase; PK‐A, cAMP‐activated protein kinase; PK‐C, phospholipid‐dependent protein kinase; PLC, phospholipase C; PP, protein phosphatase; VIP, vasoactive intestinal polypeptide.


Figure 1.

Inhibition of 125I‐CCK‐33 binding by cholecystokinin (CCK) analogues. Pancreatic membrane particles were incubated with 25 pM 125I‐CCK for 120 min in the presence or absence of various CCK analogues. Nonsaturable binding was subtracted from total binding, and saturable binding was expressed as the percent of maximal saturable binding. d‐CCK‐8, unsulfated COOH‐terminal octa‐peptide of CCK; G‐17‐II, sulfated gastrin‐17; G‐17‐I, unsulfated gastrin‐17; CCK‐4, COOH‐terminal tetrapeptide of CCK.

From Steigerwalt and Williams 157


Figure 2.

Electron‐microscopic autoradiograph of rat acini incubated for 1 h with 125I‐CCK‐33 at 37°C. Circles, silver grains overlying 125I‐CCK molecules. Note grains both on basolateral membrane and intracellularly.



Figure 3.

Autoradiograms of somatostatin (A) and CCK (B) cross‐linked to their receptors in pancreatic plasma membranes. A: 125I‐Tyr1 somatostatin was incubated in the presence or absence of 1 μM cyclic somatostatin and then cross‐linked with 0.1 mM n‐hydroxysuccinimide azidobenzoate and exposure to UV light. B: 125I‐CCK‐33 was incubated with mouse pancreatic acini in presence or absence of 0.1 μM CCK‐8 and then cross‐linked with 0.1 mM disuccinimidyl suberate. In both A and B, membranes were treated with 50 mM dithiothreitol (DTT) where specified.

A from Sakamoto et al. 142; B from Sakamoto et al. 140


Figure 4.

Time dependence of decrease in specific [3H]N‐methyl‐scopolamine (NMS) binding to guinea pig pancreatic acini cultured with 0.1 mM carbachol (open circles) or in control media (filled circles). At each indicated time, acini were rinsed and incubated for 60 min with 0.5 nM 3H]NMS.

From Hootman et al. 63


Figure 5.

Effect of Ca2+ removal on basal and caerulein‐stimulated amylase release from mouse pancreatic acini. EGTA, ethylene glycol‐bis(β‐aminoethylether)‐N,N'‐tetraacetic acid.

From Williams 179


Figure 6.

Kinetics of initial changes in [Ca2+] of pancreatic acini measured with quin 2 after stimulation by carbachol. Acini were suspended in medium containing 1.28 mM Ca2+ (A) or in medium containing 0.1 mM EGTA and no added Ca2+ (B). Concentration of carbachol shown was added at the arrow.

From Ochs et al. 108


Figure 7.

Relationship between amount of amylase released from pancreatic acini and [Ca2+]i. Release of amylase and rise in [Ca2+]i of quin 2‐loaded pancreatic acini were measured after addition of various concentrations of either carbachol (–1 μM) or inomycin (–1 μM).

From Ochs et al. 108


Figure 8.

Effect of inositol 1,4,5‐trisphosphate (IP3) on intracellular Ca2+ stores of leaky acinar cells. Calcium in the medium was measured with an ion‐selective electrode. Initial upward trace, fall in medium Ca2+ as it is taken up by acinar organelles; abrupt downward deflection, Ca2+ release induced by IP3.

From Streb et al. 161


Figure 9.

Synergism of amylase release from mouse pancreatic acini induced by the calcium ionophore A23187 2 μM) and the phorbol ester 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) 10−6 M). Together the two are able to reproduce effect of maximal concentration of carbachol (CCh).



Figure 10.

Ability of secretin, vasoactive intestinal polypeptide (VIP), and peptide histidine isoleucine (PHI) to increase cAMP in dispersed acini from guinea pig pancreas.

From Jensen et al. 76


Figure 11.

Demonstration of separate calmodulin‐ and phospholipid‐dependent, Ca2+‐activated kinase activity in mouse pancreas cytosol. Acinar cytosol was initially treated with phenothiazine coupled to a solid matrix to remove endogenous calmodulin. Cytosol was incubated with [γ‐32P]ATP in the absence (‐) or presence (+) of Ca2+ alone (A), with added calmodulin (B), or added phosphatidylserine (C) and phosphorylated proteins resolved by polyacrylamide gel electrophoresis and autoradiography. Ca2+‐activated kinase activity is present in B and C and shown to act on different endogenous substrates.

From Burnham and Williams 18


Figure 12.

Autoradiographs of polyacrylamide gels of purified zymogen granules incubated with [32P]ATP and phosphatidylserine, in the presence (+) or absence (‐) of Ca2+. A: intact purified granules. B: granules extracted with KCl prior to 32P labeling. C: granules extracted with KCl after 32P labeling.

From Burnham et al. 16


Figure 13.

Ca2+ sensitivity of Ca2+‐activated protein phosphatase activity purified from pancreatic cytosol. [32P]casein was used as a substrate. Phosphatase activity is totally dependent on presence of calmodulin (CaM). TFP, trifluoperazine.

From Burnham 14


Figure 14.

Autoradiographs of soluble proteins obtained from mouse acini that were incubated with [32P]phosphate for 60 min and stimulated with 3 μM carbachol (CCh) for 5 min. Soluble proteins were subjected to 2‐dimensional poly‐acrylamide gel electrophoresis; proteins that undergo an alteration in phosphorylation in response to carbachol are numbered and indicated by arrows. IEF, isoelectric focusing dimension; SDS, sodium dodecyl sulfate.

[From Burnham et al. 15.]


Figure 15.

Schematic diagram of stimulus‐secretion coupling of pancreatic acinar cell protein secretion. ACh, acetylcholine; CAM, calmodulin; CCK, cholecystokinin; DAG, diacylglycerol; Gs, stimulatory guanine nucleotide‐binding protein; G?, unknown guanine nucleotide‐regulated protein; IP3, inositol 1,4,5‐trisphosphate; PIP2, phosphatidylinositol 4,5‐bisphosphate; PK, protein kinase; PK‐A, cAMP‐activated protein kinase; PK‐C, phospholipid‐dependent protein kinase; PLC, phospholipase C; PP, protein phosphatase; VIP, vasoactive intestinal polypeptide.

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Article Title: Cellular Regulation of Pancreatic Secretion
 

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John A. Williams, Daniel B. Burnham, Seth R. Hootman. Cellular Regulation of Pancreatic Secretion. Compr Physiol 2011, Supplement 18: Handbook of Physiology, The Gastrointestinal System, Salivary, Gastric, Pancreatic, and Hepatobiliary Secretion: 419-441. First published in print 1989. doi: 10.1002/cphy.cp060321