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Signaling Transduction in Hormone‐ and Neurotransmitter‐Induced Enzyme Secretion from the Exocrine Pancreas

Irene Schulz

10.1002/cphy.cp060322

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 In Vitro Preparations For Studying Cellular Mechanisms
1.1 Isolated Acini and Acinar Cells
1.2 Isolation of Intracellular Organelles
2 Function of Pancreatic Cell Membranes
2.1 Transport Systems in Plasma Membrane
2.2 Role of Plasma Membranes in Hormonal Stimulation of Pancreatic Secretion
3 Role of Intracellular Membranes in Pancreatic Cell Function
3.1 Passive Ion‐Transport Mechanisms in Endoplasmic Reticulum
3.2 Active Ion‐Transport Mechanisms in Endoplasmic Reticulum
4 Ion Transport Involved in Exocytosis
4.1 Is a Chloride Conductance in the Membrane of Pancreatic Zymogen Granules Involved in Exocytosis?
Figure 1. Figure 1.

Schematic representation of primary and secondary active transport processes in the plasma membrane of pancreatic acinar cells and of Ca2+‐transport processes in intracellular organelles. AA, amino acid; ACh, acetylcholine; [Ca2+]cyt, cytosolic free Ca2+ concentration; [Ca2+]ext, external free Ca2+ concentration; CCK‐Pz cholecystokinin‐pancreozymin; DG, diacylglycerol; ER, endoplasmic reticulum; IP3, inositol 1,4,5‐trisphosphate; MIT, mitochondria; N, GTP‐binding protein; PIP2, phosphatidylinositol 4,5‐bisphosphate; PM, plasma membrane; ROC, receptor‐operated Ca2+ channel. Filled circles, primary active transport (MgATP driven); open circles, secondary active transport (electrochemical ion‐gradient driven).
Figure 2. Figure 2.

Model for the mechanism of pancreatic electrolyte and fluid secretion. Na+‐H+ antiport is located at the basal cell side coupled to the Na+ gradient that is maintained by the Na+‐K+‐ATPase. On the luminal cell side either an conductive pathway (1) or a Cl− conductive pathway combined with a Cl− exchanger (2) is present. Secretin (SN) binds to its receptor (R) and stimulates adenylate cyclase (AC) to produce cAMP that opens up conductive pathways for (1) or Cl− (2).

Model based on data from Bungaard et al. 28, Kuijpers et al. 124, Novak 161, and Schulz 196
Figure 3. Figure 3.

Schematic representation for regulation of adenylate cyclase activity. C, catalytic subunit of adenylate cyclase; CT, cholera toxin; Hi, inhibitory ligands of adenylate cyclase; Hs, stimulatory ligands of adenylate cyclase; Ni, inhibitory N protein of adenylate cyclase; Ns, stimulatory N protein of adenylate cyclase; PT, pertussis toxin; Ri, inhibitory receptor; Rs, stimulatory receptor; α,β,γ, α,β,γ‐complex of the respective N protein.
Figure 4. Figure 4.

Major pathways in agonist‐dependent phosphoinositide metabolism and sites of Li+ action. Both phosphatidic acid (PA) and myo‐inositol are synthesized from D‐glucose. Cytidine diphosphodiacylglycerol (CDP‐DG), also named cytidine monophosphorylphosphatidate (CMPPA; CMP‐PA), is formed from phosphatidic acid and CTP in the presence of CTP‐PA cytidyltransferase. Biosynthesis of phosphatidylinositol (PI) from CDP‐DG and myo‐inositol via PI‐synthetase occurs at the plasma membrane. Phosphorylation of PI by ATP in the presence of specific kinases to phosphatidylinositol 4‐phosphate (PIP) and phosphatidylinositol 4,5‐bisphosphate (PIP2) occurs at the plasma membrane. Specific phosphatases in the plasma membrane can dephosphorylate PIP2 to PIP and to PI. Agonists stimulate plasma membrane—bound phospholipase C, which leads to breakdown of phosphoinositides into diacylglycerol (DG) and water‐soluble inositol phosphates. Diacylglycerol is either metabolized via lipases to release arachidonic acid (AA) for eicosanoid biosynthesis or is phosphorylated by ATP in the presence of the plasma membrane enzyme diacylglycerol kinase to regenerate PA. The other product of phospholipase C‐mediated PIP2 hydrolysis, inositol 1,4,5‐trisphosphate [I1,4,5)P3], is degraded via a specific phosphatase to inositol 1,4‐bisphosphate [I1,4)P2] and inositol 1‐phosphate (I1P), and it is also phosphorylated via a specific kinase to inositol 1,3,4,5‐tetrakisphosphate [I1,3,4,5)P4]. Inositol 1,3,4,5‐tetrakisphosphate is dephosphorylated to inositol 1,3,4‐trisphosphate [I1,3,4)P3] and to inositol 3,4‐bisphosphate [I3,4)P2]. Another pathway might involve degradation to inositol 1,3‐bisphosphate [I1,3)P2].

Model partly based on work by Shears et al. 199 and Irvine et al. 96
Figure 5. Figure 5.

Model for coupling of receptor to phospholipase C (PLC). When an agonist binds to its receptor, bound GDP is exchanged for GTP on the α‐subunit of the Np protein. This leads to dissociation of the heterotrimer to α‐ and βγ‐subunits. Dissociation can also occur in the presence of GTPγS or (AlF4)− in the absence of an agonist. GDPβS can inhibit subunit dissociation. The dissociated GTP‐αp complex then activates phospholipase C, which catalyzes the hydrolysis of phosphatidylinositol 4,5‐bisphosphate (PIP2) to inositol 1,4,5‐trisphosphate (IP3) and diacylglycerol (DG). IP3 diffuses into the cytosol and releases Ca2+ from the endoplasmic reticulum, while diacylglycerol remains in the plasma membrane and activates protein kinase C. The α‐subunit possesses GTPase activity and so hydrolyzes the bound GTP, thus terminating the activation of phospholipase C. In the presence of GTPγS and (AlF4)−, inactivation of the α‐subunit does not occur. Phospholipase C possesses a high‐affinity site for Ca2+, which has to be occupied for α‐subunit activation. The minimum Ca2+ requirement is 100 nM, the concentration found in unstimulated cells. However, Ca2+ in the range of 1‐500 μM (depending on cell type and conditions of assay) can also stimulate phospholipase C directly without involving the Np protein. Hp, stimulatory hormone of phospholipase C; Rp, receptor of phospholipase C.

Adapted from Cockcroft 43
Figure 6. Figure 6.

Schematic diagram of the 2 signal‐transduction systems. AC, adenylate cyclase; C‐kinase, protein kinase C; DG, diacylglycerol; I1,4,5)P3, inositol 1,4,5‐trisphosphate; N, GTP‐binding protein; Ni, inhibitory N proteins; Np, N protein of phospholipase C; Ns, stimulatory N proteins; PIP2, phosphatidylinositol 4,5‐bisphosphate; PLC, phospholipase C; R, receptor; Rp, receptor of phospholipase C; Ri, inhibitory receptor of adenylate cyclase; Rs, stimulatory receptor of adenylate cyclase.
Figure 7. Figure 7.

Schematic diagram to explain patch‐clamp experiments, which give evidence for internal messenger‐activated Ca2+ influx into the cell. CCK, cholecystokinin; IP3, inositol 1,4,5‐trisphosphate; IP4, inositol 1,3,4,5‐tetrakisphosphate.

Adapted from Suzuki et al. 214
Figure 8. Figure 8.

Proposed model for coupling of stimulation with secretion of enzymes, NaCl, and fluid in pancreatic acinar cells. ACh, acetylcholine; CCK, cholecystokinin; DG, diacylglycerol; DIDS, 4,4'‐diisothiocyanatostilbene‐2,2'‐disulfonic acid; IP3, inositol 1,4,5‐trisphosphate; PIP2, phosphatidylinositol bisphosphate; PK C, protein kinase C.


Figure 1.

Schematic representation of primary and secondary active transport processes in the plasma membrane of pancreatic acinar cells and of Ca2+‐transport processes in intracellular organelles. AA, amino acid; ACh, acetylcholine; [Ca2+]cyt, cytosolic free Ca2+ concentration; [Ca2+]ext, external free Ca2+ concentration; CCK‐Pz cholecystokinin‐pancreozymin; DG, diacylglycerol; ER, endoplasmic reticulum; IP3, inositol 1,4,5‐trisphosphate; MIT, mitochondria; N, GTP‐binding protein; PIP2, phosphatidylinositol 4,5‐bisphosphate; PM, plasma membrane; ROC, receptor‐operated Ca2+ channel. Filled circles, primary active transport (MgATP driven); open circles, secondary active transport (electrochemical ion‐gradient driven).



Figure 2.

Model for the mechanism of pancreatic electrolyte and fluid secretion. Na+‐H+ antiport is located at the basal cell side coupled to the Na+ gradient that is maintained by the Na+‐K+‐ATPase. On the luminal cell side either an conductive pathway (1) or a Cl− conductive pathway combined with a Cl− exchanger (2) is present. Secretin (SN) binds to its receptor (R) and stimulates adenylate cyclase (AC) to produce cAMP that opens up conductive pathways for (1) or Cl− (2).

Model based on data from Bungaard et al. 28, Kuijpers et al. 124, Novak 161, and Schulz 196


Figure 3.

Schematic representation for regulation of adenylate cyclase activity. C, catalytic subunit of adenylate cyclase; CT, cholera toxin; Hi, inhibitory ligands of adenylate cyclase; Hs, stimulatory ligands of adenylate cyclase; Ni, inhibitory N protein of adenylate cyclase; Ns, stimulatory N protein of adenylate cyclase; PT, pertussis toxin; Ri, inhibitory receptor; Rs, stimulatory receptor; α,β,γ, α,β,γ‐complex of the respective N protein.



Figure 4.

Major pathways in agonist‐dependent phosphoinositide metabolism and sites of Li+ action. Both phosphatidic acid (PA) and myo‐inositol are synthesized from D‐glucose. Cytidine diphosphodiacylglycerol (CDP‐DG), also named cytidine monophosphorylphosphatidate (CMPPA; CMP‐PA), is formed from phosphatidic acid and CTP in the presence of CTP‐PA cytidyltransferase. Biosynthesis of phosphatidylinositol (PI) from CDP‐DG and myo‐inositol via PI‐synthetase occurs at the plasma membrane. Phosphorylation of PI by ATP in the presence of specific kinases to phosphatidylinositol 4‐phosphate (PIP) and phosphatidylinositol 4,5‐bisphosphate (PIP2) occurs at the plasma membrane. Specific phosphatases in the plasma membrane can dephosphorylate PIP2 to PIP and to PI. Agonists stimulate plasma membrane—bound phospholipase C, which leads to breakdown of phosphoinositides into diacylglycerol (DG) and water‐soluble inositol phosphates. Diacylglycerol is either metabolized via lipases to release arachidonic acid (AA) for eicosanoid biosynthesis or is phosphorylated by ATP in the presence of the plasma membrane enzyme diacylglycerol kinase to regenerate PA. The other product of phospholipase C‐mediated PIP2 hydrolysis, inositol 1,4,5‐trisphosphate [I1,4,5)P3], is degraded via a specific phosphatase to inositol 1,4‐bisphosphate [I1,4)P2] and inositol 1‐phosphate (I1P), and it is also phosphorylated via a specific kinase to inositol 1,3,4,5‐tetrakisphosphate [I1,3,4,5)P4]. Inositol 1,3,4,5‐tetrakisphosphate is dephosphorylated to inositol 1,3,4‐trisphosphate [I1,3,4)P3] and to inositol 3,4‐bisphosphate [I3,4)P2]. Another pathway might involve degradation to inositol 1,3‐bisphosphate [I1,3)P2].

Model partly based on work by Shears et al. 199 and Irvine et al. 96


Figure 5.

Model for coupling of receptor to phospholipase C (PLC). When an agonist binds to its receptor, bound GDP is exchanged for GTP on the α‐subunit of the Np protein. This leads to dissociation of the heterotrimer to α‐ and βγ‐subunits. Dissociation can also occur in the presence of GTPγS or (AlF4)− in the absence of an agonist. GDPβS can inhibit subunit dissociation. The dissociated GTP‐αp complex then activates phospholipase C, which catalyzes the hydrolysis of phosphatidylinositol 4,5‐bisphosphate (PIP2) to inositol 1,4,5‐trisphosphate (IP3) and diacylglycerol (DG). IP3 diffuses into the cytosol and releases Ca2+ from the endoplasmic reticulum, while diacylglycerol remains in the plasma membrane and activates protein kinase C. The α‐subunit possesses GTPase activity and so hydrolyzes the bound GTP, thus terminating the activation of phospholipase C. In the presence of GTPγS and (AlF4)−, inactivation of the α‐subunit does not occur. Phospholipase C possesses a high‐affinity site for Ca2+, which has to be occupied for α‐subunit activation. The minimum Ca2+ requirement is 100 nM, the concentration found in unstimulated cells. However, Ca2+ in the range of 1‐500 μM (depending on cell type and conditions of assay) can also stimulate phospholipase C directly without involving the Np protein. Hp, stimulatory hormone of phospholipase C; Rp, receptor of phospholipase C.

Adapted from Cockcroft 43


Figure 6.

Schematic diagram of the 2 signal‐transduction systems. AC, adenylate cyclase; C‐kinase, protein kinase C; DG, diacylglycerol; I1,4,5)P3, inositol 1,4,5‐trisphosphate; N, GTP‐binding protein; Ni, inhibitory N proteins; Np, N protein of phospholipase C; Ns, stimulatory N proteins; PIP2, phosphatidylinositol 4,5‐bisphosphate; PLC, phospholipase C; R, receptor; Rp, receptor of phospholipase C; Ri, inhibitory receptor of adenylate cyclase; Rs, stimulatory receptor of adenylate cyclase.



Figure 7.

Schematic diagram to explain patch‐clamp experiments, which give evidence for internal messenger‐activated Ca2+ influx into the cell. CCK, cholecystokinin; IP3, inositol 1,4,5‐trisphosphate; IP4, inositol 1,3,4,5‐tetrakisphosphate.

Adapted from Suzuki et al. 214


Figure 8.

Proposed model for coupling of stimulation with secretion of enzymes, NaCl, and fluid in pancreatic acinar cells. ACh, acetylcholine; CCK, cholecystokinin; DG, diacylglycerol; DIDS, 4,4'‐diisothiocyanatostilbene‐2,2'‐disulfonic acid; IP3, inositol 1,4,5‐trisphosphate; PIP2, phosphatidylinositol bisphosphate; PK C, protein kinase C.

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Article Title: Signaling Transduction in Hormone‐ and Neurotransmitter‐Induced Enzyme Secretion from the Exocrine Pancreas
 

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Irene Schulz. Signaling Transduction in Hormone‐ and Neurotransmitter‐Induced Enzyme Secretion from the Exocrine Pancreas. Compr Physiol 2011, Supplement 18: Handbook of Physiology, The Gastrointestinal System, Salivary, Gastric, Pancreatic, and Hepatobiliary Secretion: 443-463. First published in print 1989. doi: 10.1002/cphy.cp060322