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Cholecystokinin (CCK) Regulation of Pancreatic Acinar Cells: Physiological Actions and Signal Transduction Mechanisms

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ABSTRACT

Pancreatic acinar cells synthesize and secrete about 20 digestive enzymes and ancillary proteins with the processes that match the supply of these enzymes to their need in digestion being regulated by a number of hormones (CCK, secretin and insulin), neurotransmitters (acetylcholine and VIP) and growth factors (EGF and IGF). Of these regulators, one of the most important and best studied is the gastrointestinal hormone, cholecystokinin (CCK). Furthermore, the acinar cell has become a model for seven transmembrane, heterotrimeric G protein coupled receptors to regulate multiple processes by distinct signal transduction cascades. In this review, we briefly describe the chemistry and physiology of CCK and then consider the major physiological effects of CCK on pancreatic acinar cells. The majority of the review is devoted to the physiologic signaling pathways activated by CCK receptors and heterotrimeric G proteins and the functions they affect. The pathways covered include the traditional second messenger pathways PLC‐IP3‐Ca2+, DAG‐PKC, and AC‐cAMP‐PKA/EPAC that primarily relate to secretion. Then there are the protein‐protein interaction pathways Akt‐mTOR‐S6K, the three major MAPK pathways (ERK, JNK, and p38 MAPK), and Ca2+‐calcineurin‐NFAT pathways that primarily regulate non‐secretory processes including biosynthesis and growth, and several miscellaneous pathways that include the Rho family small G proteins, PKD, FAK, and Src that may regulate both secretory and nonsecretory processes but are not as well understood. © 2019 American Physiological Society. Compr Physiol 9:535‐564, 2019.

Figure 1. Figure 1. Two‐dimensional structure of CCK1R showing membrane spanning topology and sites of posttranslational modification. The amino terminal is outside the cell membrane and the carboxy terminal is inside. Sites of glycosylation are indicated by a Y and sites of phosphorylation by P in a circle. There is a site of palmitoylation in the carboxyl terminal tail indicated by two Cs anchored to the membrane. The natural CCK peptide is indicated as a brown oval docked to the receptor. Reproduced, with permission, from reference ().
Figure 2. Figure 2. CCK1R signals through multiple G proteins to activate different signaling cascades. Whether β‐Arrestin and Gβ/γ play a role in pancreatic acinar cells is unclear ().
Figure 3. Figure 3. Ca2+ oscillations induced by pmol/L concentrations of CCK that are initially independent of extracellular Ca2+. Ca2+ was removed and EGTA added 1 min before CCK was added. Reproduced, with permission, from reference ().
Figure 4. Figure 4. CCK initiates Ca2+ waves that travel around an acini. (A) Ca2+ signaling shown for a single cell was typical of all cells in an acinar cluster; however, they did not occur synchronously. (B) Pseudocolor image of Ca2+ concentration shows that superfusion with 20 pmol/L CCK initiates a signal in one cell that then propagates in each cell around the cluster. After a basal period, a new cycle is initiated in the same cell. Reproduced, with permission, from reference ().
Figure 5. Figure 5. Intracellular Ca2+ signaling in pancreatic acinar cells is initiated by the binding of Acetylcholine to Muscarinic M3 receptors (M3R) and by Cholecystokinin (CCK) to CCK receptors, predominately the CCK1R in mice and rats. Both receptors are classical seven transmembrane domain receptors coupled to guanine nucleotide‐binding proteins (G proteins). Activation of both receptors leads to stimulation of Gαq and increased activity of phospholipase C‐β (PLC) which cleaves the membrane phospholipid phosphatidylinositol,4,5,‐bisphosphate (PIP2) into diacylglycerol and inositol 1,4,5‐trisphosphate (IP3). IP3 diffuses through the cytoplasm and interacts with InsP3 receptors (IP3R), largely type‐2 and ‐3 present predominantly on the apical endoplasmic reticulum (ER) resulting in Ca2+ release into the cytoplasm. Ca2+ release from IP3R acts a co‐agonist to increase further IP3R activity and also acts on Ryanodine receptors (RyR) to induce Ca2+ release. Depletion of Ca2+ within the ER results in Ca2 + influx from the extracellular space. The ER Ca2+ sensor has been identified as stromal interaction molecule‐1 (Stim‐1). Following ER depletion, Ca2+ is released from an EF hand present in a domain of Stim‐1 within the ER lumen and this results in aggregation of several Stim‐1 molecules. Aggregation of Stim‐1 is sufficient to gate plasma membrane Ca2+ channels and leads to Ca2+ influx. Good candidates for the channel pore are the proteins Orai‐1 and TRPC3. CCK receptor stimulation also stimulates ADP‐ribosyl cyclase activity resulting in the formation of two additional Ca2+ mobilizing second messengers; nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic‐ADP ribose (cADPr). The particular cyclase responsible has not been defined in pancreas but good candidates include CD38 and CD157. cADPr is generally thought to act on RyR, while the target of NAADP is currently the subject of intense research. Candidates include the RyR and Two Pore Channel (TPC). In addition to the ER, Ca2+ can also be released from a store, which accumulates Ca2+ in a manner dependent on a proton gradient‐ known as the “acidic store.” This pool likely represents the endolysosomal compartment. This pool has been reported to be responsive to IP3, cADPr and NAADP and may represent the store initially released following receptor stimulation. Ca2+ is removed from the cytoplasm by the concerted action of SERCA (ER Ca2+‐ATPase), PMCA (PM Ca2+‐ATPase), and the action of MCU (mitochondrial uniporter). Figure and legend reproduced, with permission, from reference ().
Figure 6. Figure 6. Activation of PKC isoforms in pancreatic acinar cells. CCK and ACh activate PLCβ and EGF activates PLCγ all of which lead to production of diacylglycerol (DAG) from PIP2. CCK also induces DAG formation from phosphatidylcholine (PC). Ca2+ and DAG together activate the classical isoforms PKC α, β, and γ; DAG activates the novel isoforms PKC δ, ϵ, η, and θ; while unconventional isoforms PKC ζ and λ do not require Ca2+ or DAG. Reproduced, with permission, from Pancreapedia, DAG–PKC Signaling Pathway, 2013.
Figure 7. Figure 7. Parallel nature of MAPK cascades in pancreas. Modified and updated, with permission, from reference ().
Figure 8. Figure 8. Activation of ERK signaling pathway by CCK and EGF in pancreatic acinar cells. CCK1R signals through PKC and the activation by phosphorylation of Raf isoforms. Raf sequentially phosphorylates and activates MEK1/2 and ERK1/2. By contrast, EGFR autophosphorylates and then binds Shc, Grb2 and SOS with the latter being a GEF for Ras; active Ras binds and activates Raf and the kinase cascade ending in ERK. Activated ERK phosphorylates cytoplasmic substrates and downstream kinases, which phosphorylates transcription factors thereby activating expression of specific genes. Reproduced, with permission, from reference ().
Figure 9. Figure 9. General and simplified diagram of mTORC1 pathway set in pancreatic acinar cell, where the pathway is regulated by CCK and insulin. Red arrows indicate activation; Black arrows indicate inhibition; Green arrow indicates translocation. Biological processes regulated by mTORC1 are shown at the bottom of the figure, along with the key proteins mediating the effect. Reproduced, with permission, from reference ().
Figure 10. Figure 10. Activation of the Ca2+‐calcineurin‐NFAT signaling pathway by CCK and cholinergic agonists in pancreatic acinar cells. The initial steps in the pathway involve receptor‐mediated elevation of intracellular Ca2+. Ca2+ binds to calmodulin (CaM) and the complex to the Ca2 + activated phosphatase calcineurin. Calcineurin can dephosphorylate a number of substrates but the most generally important are NFATS which when dephosphorylated move into the nucleus and bind alone or together with coactivators such as AP‐1 to activate specific genes including FGF21, Socs3, Rgs2, Hbegf and Rcan1 with the latter feeding back to inhibit calcineurin. Reproduced, with permission, from the Pancreapedia, Calcium–Calcineurin–NFAT Signaling Pathway, 2012.
Figure 11. Figure 11. Rho Activation pathway by CCK and ACh. The CCK1 and muscarinic M3 receptors activate Gα12/13, which activate a Rho GEF of which several present in the pancreas are shown. Rho with bound GTP can activate mDia1 or ROCK (Rho kinase) thereby regulating the actin cytoskeleton or activate SRF (serum response factor) and activate gene expression. GTP bound Rho is inactivated by a Rho GAP of which several present in pancreas are shown. Botulinum exotoxin can permanently inactivate Rho. Reproduced, with permission, from Pancreapedia, Galpha12/13‐Rho Signaling Pathway, 2010.
Figure 12. Figure 12. Activation of cAMP pathway in pancreatic acinar and duct cells. Secretin, VIP and CCK bind to their receptors which activate adenylyl cyclase (AC) through Gαs while Somatostatin acts on SomstostatinR2 to activate Gαi which inhibits AC. Cholera toxin activates Gαs while forskolin directly activates AC and Pertussis toxin inhibits Gαi. AC produces cyclic AMP (cAMP) which is broken down by phosphodiesterase (PDE) which can be inhibited by isobutylmethylxanthine (IBMX). cAMP activates PKA which can phosphorylate a number of proteins including CREB, CFTR and the IP3 receptor. cAMP also activates EPAC1 which acts as a GEF to activate the small G protein Rap1 present on zymogen granules. Reproduced, with permission, from Pancreapedia, cAMP Signaling Pathway, 2012.


Figure 1. Two‐dimensional structure of CCK1R showing membrane spanning topology and sites of posttranslational modification. The amino terminal is outside the cell membrane and the carboxy terminal is inside. Sites of glycosylation are indicated by a Y and sites of phosphorylation by P in a circle. There is a site of palmitoylation in the carboxyl terminal tail indicated by two Cs anchored to the membrane. The natural CCK peptide is indicated as a brown oval docked to the receptor. Reproduced, with permission, from reference ().


Figure 2. CCK1R signals through multiple G proteins to activate different signaling cascades. Whether β‐Arrestin and Gβ/γ play a role in pancreatic acinar cells is unclear ().


Figure 3. Ca2+ oscillations induced by pmol/L concentrations of CCK that are initially independent of extracellular Ca2+. Ca2+ was removed and EGTA added 1 min before CCK was added. Reproduced, with permission, from reference ().


Figure 4. CCK initiates Ca2+ waves that travel around an acini. (A) Ca2+ signaling shown for a single cell was typical of all cells in an acinar cluster; however, they did not occur synchronously. (B) Pseudocolor image of Ca2+ concentration shows that superfusion with 20 pmol/L CCK initiates a signal in one cell that then propagates in each cell around the cluster. After a basal period, a new cycle is initiated in the same cell. Reproduced, with permission, from reference ().


Figure 5. Intracellular Ca2+ signaling in pancreatic acinar cells is initiated by the binding of Acetylcholine to Muscarinic M3 receptors (M3R) and by Cholecystokinin (CCK) to CCK receptors, predominately the CCK1R in mice and rats. Both receptors are classical seven transmembrane domain receptors coupled to guanine nucleotide‐binding proteins (G proteins). Activation of both receptors leads to stimulation of Gαq and increased activity of phospholipase C‐β (PLC) which cleaves the membrane phospholipid phosphatidylinositol,4,5,‐bisphosphate (PIP2) into diacylglycerol and inositol 1,4,5‐trisphosphate (IP3). IP3 diffuses through the cytoplasm and interacts with InsP3 receptors (IP3R), largely type‐2 and ‐3 present predominantly on the apical endoplasmic reticulum (ER) resulting in Ca2+ release into the cytoplasm. Ca2+ release from IP3R acts a co‐agonist to increase further IP3R activity and also acts on Ryanodine receptors (RyR) to induce Ca2+ release. Depletion of Ca2+ within the ER results in Ca2 + influx from the extracellular space. The ER Ca2+ sensor has been identified as stromal interaction molecule‐1 (Stim‐1). Following ER depletion, Ca2+ is released from an EF hand present in a domain of Stim‐1 within the ER lumen and this results in aggregation of several Stim‐1 molecules. Aggregation of Stim‐1 is sufficient to gate plasma membrane Ca2+ channels and leads to Ca2+ influx. Good candidates for the channel pore are the proteins Orai‐1 and TRPC3. CCK receptor stimulation also stimulates ADP‐ribosyl cyclase activity resulting in the formation of two additional Ca2+ mobilizing second messengers; nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic‐ADP ribose (cADPr). The particular cyclase responsible has not been defined in pancreas but good candidates include CD38 and CD157. cADPr is generally thought to act on RyR, while the target of NAADP is currently the subject of intense research. Candidates include the RyR and Two Pore Channel (TPC). In addition to the ER, Ca2+ can also be released from a store, which accumulates Ca2+ in a manner dependent on a proton gradient‐ known as the “acidic store.” This pool likely represents the endolysosomal compartment. This pool has been reported to be responsive to IP3, cADPr and NAADP and may represent the store initially released following receptor stimulation. Ca2+ is removed from the cytoplasm by the concerted action of SERCA (ER Ca2+‐ATPase), PMCA (PM Ca2+‐ATPase), and the action of MCU (mitochondrial uniporter). Figure and legend reproduced, with permission, from reference ().


Figure 6. Activation of PKC isoforms in pancreatic acinar cells. CCK and ACh activate PLCβ and EGF activates PLCγ all of which lead to production of diacylglycerol (DAG) from PIP2. CCK also induces DAG formation from phosphatidylcholine (PC). Ca2+ and DAG together activate the classical isoforms PKC α, β, and γ; DAG activates the novel isoforms PKC δ, ϵ, η, and θ; while unconventional isoforms PKC ζ and λ do not require Ca2+ or DAG. Reproduced, with permission, from Pancreapedia, DAG–PKC Signaling Pathway, 2013.


Figure 7. Parallel nature of MAPK cascades in pancreas. Modified and updated, with permission, from reference ().


Figure 8. Activation of ERK signaling pathway by CCK and EGF in pancreatic acinar cells. CCK1R signals through PKC and the activation by phosphorylation of Raf isoforms. Raf sequentially phosphorylates and activates MEK1/2 and ERK1/2. By contrast, EGFR autophosphorylates and then binds Shc, Grb2 and SOS with the latter being a GEF for Ras; active Ras binds and activates Raf and the kinase cascade ending in ERK. Activated ERK phosphorylates cytoplasmic substrates and downstream kinases, which phosphorylates transcription factors thereby activating expression of specific genes. Reproduced, with permission, from reference ().


Figure 9. General and simplified diagram of mTORC1 pathway set in pancreatic acinar cell, where the pathway is regulated by CCK and insulin. Red arrows indicate activation; Black arrows indicate inhibition; Green arrow indicates translocation. Biological processes regulated by mTORC1 are shown at the bottom of the figure, along with the key proteins mediating the effect. Reproduced, with permission, from reference ().


Figure 10. Activation of the Ca2+‐calcineurin‐NFAT signaling pathway by CCK and cholinergic agonists in pancreatic acinar cells. The initial steps in the pathway involve receptor‐mediated elevation of intracellular Ca2+. Ca2+ binds to calmodulin (CaM) and the complex to the Ca2 + activated phosphatase calcineurin. Calcineurin can dephosphorylate a number of substrates but the most generally important are NFATS which when dephosphorylated move into the nucleus and bind alone or together with coactivators such as AP‐1 to activate specific genes including FGF21, Socs3, Rgs2, Hbegf and Rcan1 with the latter feeding back to inhibit calcineurin. Reproduced, with permission, from the Pancreapedia, Calcium–Calcineurin–NFAT Signaling Pathway, 2012.


Figure 11. Rho Activation pathway by CCK and ACh. The CCK1 and muscarinic M3 receptors activate Gα12/13, which activate a Rho GEF of which several present in the pancreas are shown. Rho with bound GTP can activate mDia1 or ROCK (Rho kinase) thereby regulating the actin cytoskeleton or activate SRF (serum response factor) and activate gene expression. GTP bound Rho is inactivated by a Rho GAP of which several present in pancreas are shown. Botulinum exotoxin can permanently inactivate Rho. Reproduced, with permission, from Pancreapedia, Galpha12/13‐Rho Signaling Pathway, 2010.


Figure 12. Activation of cAMP pathway in pancreatic acinar and duct cells. Secretin, VIP and CCK bind to their receptors which activate adenylyl cyclase (AC) through Gαs while Somatostatin acts on SomstostatinR2 to activate Gαi which inhibits AC. Cholera toxin activates Gαs while forskolin directly activates AC and Pertussis toxin inhibits Gαi. AC produces cyclic AMP (cAMP) which is broken down by phosphodiesterase (PDE) which can be inhibited by isobutylmethylxanthine (IBMX). cAMP activates PKA which can phosphorylate a number of proteins including CREB, CFTR and the IP3 receptor. cAMP also activates EPAC1 which acts as a GEF to activate the small G protein Rap1 present on zymogen granules. Reproduced, with permission, from Pancreapedia, cAMP Signaling Pathway, 2012.
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Teaching Material

J. A. Williams. Cholecystokinin (CCK) Regulation of Pancreatic Acinar Cells: Physiological Actions and Signal Transduction Mechanisms. Compr Physiol 9: 2019, 535-564.

Didactic Synopsis

Major Teaching Points:

  • Cholecystokinin (CCK) is a peptide hormone and paracrine regulator produced in unique intestinal enteroendocrine cells and specific neurons in the brain.
  • The major targets for CCK regulation in the gastrointestinal tract are the pancreatic acinar cell which is stimulated to secrete, gallbladder smooth muscle which contracts and gastric smooth muscle which is relaxed to inhibit gastric emptying.
  • The actions of CCK on pancreatic acinar cells are mediated by CCK type1 receptors, heterotrimeric G proteins and signal transduction pathways.
  • Acinar cell digestive enzyme secretion is mediated by the traditional second messenger pathways centered on Ca2+, cAMP, and diacylglycerol – PKC.
  • Distinct pathways regulating pancreatic adaptive growth and gene expression are mediated by mTOR, the three MAPK pathways centered on ERK, JNK, and p38MAPK as well as the calcineurin – NFAT.
  • Small G proteins Rho and Rac are activated by CCK and affect both secretory and nonsecretory processes.
  • Other signaling proteins that can be activated by CCK include PKD, Src, and FAK.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching Points. The primary linear amino acid sequence (without most individual amino acids) is shown for the CCK1 Receptor as it is organized through the plasma membrane in two-dimensions.

Figure 2 Teaching Points. This diagram illustrates how the CCK1R can initiate multiple signaling pathways by activating different heterotrimeric G proteins including three different alpha subunits and possibly the beta/gamma subunits.

Figure 3 Teaching Points. A record of changes in intracellular Ca2+ concentrations recorded from a single cell by fura 2 flourescence when a pancreatic acinar cell in vitro is stimulated with a physiological concentration of CCK. Note that the transient increases in Ca2+ termed oscillations are maintained for 10 min in the absence of external calcium.

Figure 4 Teaching Points. This figure shows intracellular Ca2+ concentrations in cells of a pancreatic acini as a digital image with color coding to represent the concentration of Ca2+. At any one point in an acini the calcium concentration shows oscillations as shown in panel A. Panel B shows a rise in calcium concentration in a region of one cell that spreads to an adjacent cell through gap junctions and on around the acini. After a resting basal period a new cycle is initiated.

Figure 5 Teaching Points. Summary diagram of intracellular Ca2+ signaling in the pancreatic acinar cell and the protein and lipid molecules and the intracellular organells that are involved. The diagram can be used to trace the intracellular pathway from receptors to elevation of intracellular free Ca2+ and zymogen granule exocytosis. Details are given in the regular figure legend.

Figure 6 Teaching Points. This diagram illustrates the diacylglycerol – Protein kinase C signaling pathway leading to the activation of specific PKC isoforms.

Figure 7 Teaching Points. This diagram shows the three main mitogen activated protein kinase pathways activated by the CCK receptor. The mechanism for how each pathway is activated is only understood for the ERK pathway as shown in Fig. 8. The bottom of each pathway in Figure 7 shows proteins activated by that particular MAPK.

Figure 8 Teaching Points. This diagram shows mechanisms for CCK and epidermal growth factor (EGF) to activate the ERK pathway in pancreatic acinar cells.

Figure 9 Teaching Points. This diagram shows how CCK and insulin activate the mammalian target of rapamycin complex 1 pathway (mTORC1) in acinar cells. Activation of TORC1 in model cells involves translocation to the lysosomal surface where other proteins can activate it. The bottom of the drawing shows proteins and fucnctions regulated by TORC1 most of which has been shown to occur in acinar cells.

Figure 10 Teaching Points. This diagram shows how the calcineurin – NFAT pathway is activated by CCK and acetylcholine (Ach) in acinar cells. It also shows how Rho regulates the actin cytoskeleton and gene expression.

Figure 11 Teaching Points. This diagram shows how the small G protein Rho is activated by CCK and Ach in acinar cells. It also shows how Rho regulates the actin cytoskeleton and gene expression.

Figure 12 Teaching Points. This diagram shows how receptors for GI hormones regulate Adenylyl cyclase and the formation of cAMP. While the primary activators are secretin and VIP whose receptors activate Gαs, the CCK1R can also activate to a limited degree. Somatostatin inhibits adenylyl cyclase through Gαi. The figure also shows how cAMP activates PKA and EPAC1 and thereby effects exocytosis and chloride (fluid) secretion. Details are given in the regular figure legends.

 


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How to Cite

John A. Williams. Cholecystokinin (CCK) Regulation of Pancreatic Acinar Cells: Physiological Actions and Signal Transduction Mechanisms. Compr Physiol 2019, 9: 535-564. doi: 10.1002/cphy.c180014