scholarly journals Src kinases play a novel dual role in acute pancreatitis affecting severity but no role in stimulated enzyme secretion

2016 ◽  
Vol 310 (11) ◽  
pp. G1015-G1027 ◽  
Author(s):  
Bernardo Nuche-Berenguer ◽  
Irene Ramos-Álvarez ◽  
R. T. Jensen
Keyword(s):  
Acute Pancreatitis ◽  
Map Kinases ◽  
Severe Disease ◽  
Acinar Cells ◽  
Dual Role ◽  
Enzyme Secretion ◽  
Pancreatic Acinar Cells ◽  
Enzyme Release ◽  
Amylase Release ◽  
Pancreatic Acini

In pancreatic acinar cells, the Src family of kinases (SFK) is involved in the activation of several signaling cascades that are implicated in mediating cellular processes (growth, cytoskeletal changes, apoptosis). However, the role of SFKs in various physiological responses such as enzyme secretion or in pathophysiological processes such as acute pancreatitis is either controversial, unknown, or incompletely understood. To address this, in this study, we investigated the role/mechanisms of SFKs in acute pancreatitis and enzyme release. Enzyme secretion was studied in rat dispersed pancreatic acini, in vitro acute-pancreatitis-like changes induced by supramaximal COOH-terminal octapeptide of cholecystokinin (CCK). SFK involvement assessed using the chemical SFK inhibitor (PP2) with its inactive control, 4-amino-7-phenylpyrazol[3,4-d]pyrimidine (PP3), under experimental conditions, markedly inhibiting SFK activation. In CCK-stimulated pancreatic acinar cells, activation occurred of trypsinogen, various MAP kinases (p42/44, JNK), transcription factors (signal transducer and activator of transcription-3, nuclear factor-κB, activator protein-1), caspases (3, 8, and 9) inducing apoptosis, LDH release reflective of necrosis, and various chemokines secreted (monocyte chemotactic protein-1, macrophage inflammatory protein-1α, regulated on activation, normal T cell expressed and secreted). All were inhibited by PP2, not by PP3, except caspase activation leading to apoptosis, which was increased, and trypsin activation, which was unaffected, as was CCK-induced amylase release. These results demonstrate SFK activation is playing a dual role in acute pancreatitis, inhibiting apoptosis and promoting necrosis as well as chemokine/cytokine release inducing inflammation, leading to more severe disease, as well as not affecting secretion. Thus, our studies indicate that SFK is a key mediator of inflammation and pancreatic acinar cell death in acute pancreatitis, suggesting it could be a potential therapeutic target in acute pancreatitis.

Expression of NK-1 and NK-3 tachykinin receptors in pancreatic acinar cells after acute experimental pancreatitis in rats

2006 ◽  
Vol 291 (3) ◽  
pp. G518-G524 ◽  
Author(s):  
Maria Broccardo ◽  
Giorgio Linari ◽  
Simona Agostini ◽  
Giusi Amadoro ◽  
Francesco Carpino ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Substance P ◽  
Acinar Cells ◽  
Receptor Expression ◽  
Pancreatic Acinar Cells ◽  
Morphological Evidence ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Tachykinin Receptors ◽  
New Findings

Activation of neurokinin (NK)-1 receptors but not of NK-3 stimulates amylase release from isolated pancreatic acini of the rat. Immunofluorescence studies show that NK-1 receptors are more strongly expressed than NK-3 receptors on pancreatic acinar cells under basal conditions. No studies have examined the expression of the two NK receptor populations in pancreatic acini during pancreatitis in rats. We therefore investigated the relationships between expression of these two tachykinin receptors and experimental acute pancreatitis induced by stimulating pancreatic amylase with caerulein (CK) in rats. Hyperstimulation of the pancreas by CK caused an increase in plasma amylase and pancreatic water content and resulted in morphological evidence of cytoplasmic vacuolization. Immunofluorescence analysis revealed a similar percentage of NK-1 receptor antibody immunoreactive acinar cells in rats with pancreatitis and in normal rat tissue but a larger percentage of NK-3 receptor immunoreactive cells in acute pancreatitis than in normal pancreas. Western blot analysis of NK-1 and NK-3 receptor protein levels after CK-induced pancreatitis showed no change in NK-1 receptors but a stronger increase in NK-3 receptor expression in pancreatic acini compared with normal rats thus confirming the immunofluorescence data. These new findings support previous evidence that substance P-mediated functions within the pancreas go beyond sensory signal transduction contributing to neurogenic inflammation, and they suggest that substance P plays a role in regulating pancreatic exocrine secretion via acinar NK-1 receptors. The significant increase in NK-3 receptors during pancreatic stimulation suggests that NK-3 receptors also intervene in the pathogenesis of mild acute pancreatitis in rats.

Substance P treatment stimulates chemokine synthesis in pancreatic acinar cells via the activation of NF-κB

2006 ◽  
Vol 291 (6) ◽  
pp. G1113-G1119 ◽  
Author(s):  
Raina Devi Ramnath ◽  
Madhav Bhatia
Keyword(s):  
Acute Pancreatitis ◽  
Substance P ◽  
Acinar Cell ◽  
Cell Injury ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Acinar Cells ◽  
Chemokine Production ◽  
Pancreatic Acini ◽  
Monocyte Chemoattractant Protein 1

Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction and to the subsequent systemic inflammatory response, which may result in multiple organ dysfunction and death. Inflammatory mediators, including chemokines and substance P (SP), are known to play a crucial role in the pathogenesis of acute pancreatitis. It has been shown that pancreatic acinar cells produce the chemokine monocyte chemoattractant protein-1 (MCP-1) in response to caerulein hyperstimulation, demonstrating that acinar-derived MCP-1 is an early mediator of inflammation in acute pancreatitis. Similarly, SP levels in the pancreas and pancreatic acinar cell expression of neurokinin-1 receptor, the primary receptor for SP, are both increased during secretagogue-induced experimental pancreatitis. This study aims to examine the functional consequences of exposing mouse pancreatic acinar cells to SP and to determine whether it leads to proinflammatory signaling, such as production of chemokines. Exposure of mouse pancreatic acini to SP significantly increased synthesis of MCP-1, macrophage inflammatory protein-1α (MIP-1α), as well as MIP-2. Furthermore, SP also increased NF-κB activation. The stimulatory effect of SP was specific to chemokine synthesis through the NF-κB pathway, since the increase in chemokine production was completely attenuated when pancreatic acini were pretreated with the selective NF-κB inhibitor NF-κB essential modulator-binding domain peptide. This study shows that SP-induced chemokine synthesis in mouse pancreatic acinar cells is NF-κB dependent.

scholarly journals Glucagon-like peptide-1 receptor is present in pancreatic acinar cells and regulates amylase secretion through cAMP

2016 ◽  
Vol 310 (1) ◽  
pp. G26-G33 ◽  
Author(s):  
Yanan Hou ◽  
Stephen A. Ernst ◽  
Kaeli Heidenreich ◽  
John A. Williams
Keyword(s):  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Amylase Secretion ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
The Central Nervous System ◽  
Central Nervous System Stimulation ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Increase Insulin Secretion

Glucagon-like peptide-1 (GLP-1) is a glucoincretin hormone that can act through its receptor (GLP-1R) on pancreatic β-cells and increase insulin secretion and production. GLP-1R agonists are used clinically to treat type 2 diabetes. GLP-1 may also regulate the exocrine pancreas at multiple levels, including inhibition through the central nervous system, stimulation indirectly through insulin, and stimulation directly on acinar cells. However, it has been unclear whether GLP-1R is present in pancreatic acini and what physiological functions these receptors regulate. In the current study we utilized GLP-1R knockout (KO) mice to study the role of GLP-1R in acinar cells. RNA expression of GLP-1R was detected in acutely isolated pancreatic acini. Acinar cell morphology and expression of digestive enzymes were not affected by loss of GLP-1R. GLP-1 induced amylase secretion in wild-type (WT) acini. In GLP-1R KO mice, this effect was abolished, whereas vasoactive intestinal peptide-induced amylase release in KO acini showed a pattern similar to that in WT acini. GLP-1 stimulated cAMP production and increased protein kinase A-mediated protein phosphorylation in WT acini, and these effects were absent in KO acini. These data show that GLP-1R is present in pancreatic acinar cells and that GLP-1 can regulate secretion through its receptor and cAMP signaling pathway.

scholarly journals Involvement of myristoylated alanine-rich C kinase substrate phosphorylation and translocation in cholecystokinin-induced amylase release in rat pancreatic acini

2016 ◽  
Vol 310 (6) ◽  
pp. G399-G409 ◽  
Author(s):  
Keitaro Satoh ◽  
Takanori Narita ◽  
Osamu Katsumata-Kato ◽  
Hiroshi Sugiya ◽  
Yoshiteru Seo
Keyword(s):  
Membrane Trafficking ◽  
Acinar Cells ◽  
Cell Types ◽  
Pancreatic Acinar Cells ◽  
Gastrointestinal Hormone ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Kinase Substrate ◽  
Translocation Assay ◽  
Triton X

Cholecystokinin (CCK) is a gastrointestinal hormone that induces exocytotic amylase release in pancreatic acinar cells. The activation of protein kinase C (PKC) is involved in the CCK-induced pancreatic amylase release. Myristoylated alanine-rich C kinase substrate (MARCKS) is a ubiquitously expressed substrate of PKC. MARCKS has been implicated in membrane trafficking in several cell types. The phosphorylation of MARCKS by PKC results in the translocation of MARCKS from the membrane to the cytosol. Here, we studied the involvement of MARCKS in the CCK-induced amylase release in rat pancreatic acini. Employing Western blotting, we detected MARCKS protein in the rat pancreatic acini. CCK induced MARCKS phosphorylation. A PKC-δ inhibitor, rottlerin, inhibited the CCK-induced MARCKS phosphorylation and amylase release. In the translocation assay, we also observed CCK-induced PKC-δ activation. An immunohistochemistry study showed that CCK induced MARCKS translocation from the membrane to the cytosol. When acini were lysed by a detergent, Triton X-100, CCK partially induced displacement of the MARCKS from the GM1a-rich detergent-resistant membrane fractions (DRMs) in which Syntaxin2 is distributed. A MARCKS-related peptide inhibited the CCK-induced amylase release. These findings suggest that MARCKS phosphorylation by PKC-δ and then MARCKS translocation from the GM1a-rich DRMs to the cytosol are involved in the CCK-induced amylase release in pancreatic acinar cells.

Relation between free cytosolic calcium and amylase release by pancreatic acini

1985 ◽  
Vol 249 (3) ◽  
pp. G389-G398 ◽  
Author(s):  
D. L. Ochs ◽  
J. I. Korenbrot ◽  
J. A. Williams
Keyword(s):  
Acinar Cells ◽  
Cytosolic Calcium ◽  
Pancreatic Acinar Cells ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Intracellular Ca ◽  
Free Media ◽  
Induced Changes ◽  
Stoichiometric Relation ◽  
Stimulation Of

Pancreatic acini were loaded with the Ca-selective fluorescent indicator quin-2 by incubation with its acetyoxymethyl ester. Loading acini with 844 +/- 133 microM quin-2 altered neither their ultrastructure nor their viability. The rate of amylase release from quin-2-loaded acini in response to the secretagogue carbachol, however, was significantly smaller than that of control acini. Studies in which acini were loaded with both quin-2 and a similar Ca-chelating compound, BAPTA, indicated that this reduced amylase release was related to the Ca buffering properties of quin-2. The concentration of free intracellular Ca calculated from the fluorescence of quin-2 was 90 +/- 18 nM. Stimulation by carbachol of acini suspended in media containing 1.25 mM Ca caused a rapid, transient enhancement of this value. After stimulation amylase release, the onset of the rise in free cytosolic Ca levels was observed in 1.1 +/- 0.1 s following the addition of agonist, and peak Ca levels (545 +/- 112 nM) were obtained within 5.3 +/- 0.3 s. For concentrations of carbachol less than or equal to 10(-6) M, a stoichiometric relation was found between stimulated amylase release and the peak concentration of free cytosolic Ca achieved. At higher concentrations of carbachol, however, the peak free cytosolic Ca remained constant while amylase release declined. The latency of the rise in intracellular Ca following stimulation of acini suspended in Ca-free media was not different from that observed for acini suspended in normal media, but the rise time was significantly prolonged. In the presence of extracellular Ca, the intracellular level of Ca remained elevated 2.8-fold above basal levels for at least 15 min following stimulation with 10(-6) M carbachol, whereas it had returned to near resting levels by 15 min when either 3 X 10(-7) or 3 X 10(-5) M carbachol was the stimulus. The Ca ionophore ionomycin (10–6 M) induced changes in the level of free cytosolic Ca similar to those caused by 10(-6) M carbachol. Ionomycin, however, stimulated only approximately one-third as much amylase release. These data suggest that factors in addition to changes in free cytosolic Ca may be important in regulating enzyme secretion by pancreatic acinar cells.

scholarly journals Comprehensive analysis of microRNA signature of mouse pancreatic acini: overexpression of miR-21-3p in acute pancreatitis

2016 ◽  
Vol 311 (5) ◽  
pp. G974-G980 ◽  
Author(s):  
Ajay Kumar Dixit ◽  
Anne E. Sarver ◽  
Zuobiao Yuan ◽  
John George ◽  
Usman Barlass ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Mouse Models ◽  
Expression Profile ◽  
Mirna Expression ◽  
Acinar Cells ◽  
Mirna Expression Profile ◽  
Comprehensive Analysis ◽  
Pancreatic Acinar Cells ◽  
Pancreatic Acini ◽  
Severity Of The Disease

In the current study, we have characterized the global miRNA expression profile in mouse pancreatic acinar cells and during acute pancreatitis using next-generation RNA sequencing. We identified 324 known and six novel miRNAs that are expressed in mouse pancreatic acinar cells. In the basal state, miR-148a-3p, miR-375-3p, miR-217-5p, and miR-200a-3p were among the most abundantly expressed, whereas miR-24-5p and miR-421-3p were the least abundant. Treatment of acinar cells with caerulein (100 nM) and taurolithocholic acid 3-sulfate [TLC-S (250 μM)] induced numerous changes in miRNA expression profile. In particular, we found significant overexpression of miR-21-3p in acini treated with caerulein and TLC-S. We further looked at the expression of miR-21-3p in caerulein, l-arginine, and caerulein + LPS-induced acute pancreatitis mouse models and found 12-, 21-, and 50-fold increased expression in the pancreas, respectively. In summary, this is the first comprehensive analysis of global miRNA expression profile of mouse pancreatic acinar cells in normal and disease conditions. Our analysis shows that miR-21-3p expression level correlates with the severity of the disease.

Impairment of Intracellular Calcium Homoeostasis in the Exocrine Pancreas after Caerulein-Induced Acute Pancreatitis in the Rat

1996 ◽  
Vol 91 (3) ◽  
pp. 365-369 ◽  
Author(s):  
M. J. Bragado ◽  
J. I. San Roman ◽  
A. González ◽  
L. J. García ◽  
M. A. López ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Intracellular Calcium ◽  
Ionized Calcium ◽  
Pancreatic Acinar Cells ◽  
Amylase Secretion ◽  
Maximal Increase ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Cholecystokinin Octapeptide ◽  
Clear Dose Response

1. We have measured intracellular calcium concentrations in basal conditions and in response to cholecystokinin-octapeptide and acetylcholine in pancreatic acini isolated from rats with caerulein-induced acute pancreatitis and compared them with those in control rats. 2. We also measured amylase secretion in basal conditions and in response to cholecystokinin-octapeptide in both groups. 3. In pancreatic acini from rats with pancreatitis the basal intracellular calcium concentration was significantly increased (134.9±7.1 nmol/l compared with 71.8 ± 2.9 nmol/l, P < 0.001). Moreover, the maximum values of intracellular calcium attained during the stimulation period were equivalent in acini from control and pancreatitic rats with no statistically significant differences. 4. In acini from control rats the differences between the resting levels of intracellular calcium and the maximum intracellular calcium values (Δ[Ca2+]i) in response to several concentrations of cholecystokinin-octapeptide showed a clear dose—response relationship, with a half-maximal increase at 0.1 nmol/l and a maximal difference (Δ[Ca2+]i = 259 ±50 nmol/l) at 1 nmol/l. In contrast, a right-shifted response, with a statistically significant smaller increase, was observed in acini from pancreatitic rats. 5. Basal amylase release was significantly higher in acini from rats with pancreatitis (11.7 ±1.0% of total compared with 5.9 ±1.1% of total, P < 0.001). In contrast, cholecystokinin-octapeptide and acetylcholine-evoked amylase secretion was reduced by more than 85% in acini from pancreatitic rats. 6. In conclusion, calcium homoeostasis in pancreatic acinar cells from rats with caerulein-induced pancreatitis seems to be impaired. These results suggest excessive release of acinar free ionized calcium, or damage to the integrity of mechanisms that restore low resting levels of intracellular free ionized calcium, and the consequent calcium toxicity could be the key trigger in caerulein-induced acute pancreatitis.

Tyrphostins inhibit secretagogue-induced 1,4,5-IP3 production and amylase release in pancreatic acini

1994 ◽  
Vol 266 (3) ◽  
pp. G363-G371
Author(s):  
A. Piiper ◽  
D. Stryjek-Kaminska ◽  
J. Stein ◽  
W. F. Caspary ◽  
S. Zeuzem
Keyword(s):  
Tyrosine Phosphorylation ◽  
Phosphorylation Site ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Amylase Secretion ◽  
Specific Cell ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Cholecystokinin Octapeptide ◽  
Permeabilized Cells

We examined the role of protein tyrosine kinase inhibitors (tyrphostins) in secretagogue-induced inositol 1,4,5-trisphosphate (1,4,5-IP3) production and amylase secretion in rat pancreatic acinar cells. The data show that various specific cell-permeant tyrphostins (methyl 2,5-dihydroxycinnamate, tyrphostin 25, and genistein) inhibited the cholecystokinin octapeptide-, carbachol-, and bombesin-induced 1,4,5-IP3 production and amylase release. In digitonin-permeabilized cells, tyrphostins decreased 1,4,5-IP3 accumulation and amylase release generated by directly stimulating G proteins with the weakly hydrolyzable GTP analogue guanosine 5'-O-(3-thiotriphosphate). Tyrphostins had no effect on vasoactive intestinal peptide-induced amylase secretion. In isolated pancreatic acinar membranes, cholecystokinin octapeptide caused a rapid increase in tyrosine phosphorylation of a synthetic peptide containing the 12-amino acid sequence around a tyrosine phosphorylation site in pp6osrc. These results provide evidence that tyrosine kinases are involved in the activation of phospholipase C by G protein-coupled receptors in pancreatic acinar cells.

Characterization of sustained [Ca2+]i increase in pancreatic acinar cells and its relation to amylase secretion

1990 ◽  
Vol 259 (5) ◽  
pp. G792-G801 ◽  
Author(s):  
Y. Tsunoda ◽  
E. L. Stuenkel ◽  
J. A. Williams
Keyword(s):  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Amylase Secretion ◽  
Cytosolic Ph ◽  
Cell Stimulation ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Fura 2 ◽  
Plateau Level

The sustained increase in cytosolic free Ca2+ concentration ([Ca2+]i) during maximal stimulation of rat pancreatic acini with carbamylcholine (10(-5) M) was investigated in individual acinar cells by microspectrofluorometric analysis of fura-2. After the large initial [Ca2+]i increase from intracellular stores, [Ca2+]i remained significantly elevated as long as the stimulus was applied. The amplitude of this plateau was dependent on the median Ca2+ concentration ([Ca2+]o) being 45-50 nM above prestimulation in medium with 1 mM [Ca2+]o increasing to 90 nM at 10 mM [Ca2+]o. This Ca2+ plateau was completely blocked by 2.5 mM Ni2+ and 0.25 mM La3+ but was unaffected by elevated K+ or the Ca2+ channel blocker D 600. Mn2+ was able to enter the cytosol after the cell stimulation as indicated by intracellular quenching of fura-2, indicating that acinar cells possess a Mn2(+)-permeable Ca2+ channel. Elimination of [Ca2+]o or addition of Ni2+ and Mn2+ to the medium reduced the level of sustained amylase secretion in a reversible manner under superfusion conditions. Increasing [Ca2+]i above the normal level by increasing [Ca2+]o had no effect on amylase secretion. The process for sustained Ca2+ entry was pH sensitive; decreasing extracellular pH (pHo) to 6.5-6.8 during the cell stimulation resulted in a reduction of the sustained [Ca2+]i plateau level and a decrease in sustained amylase secretion. By contrast, increasing pHo to 8.0 enhanced the level of the sustained [Ca2+]i in a Ni2(+)-sensitive manner but did not increase amylase release. Changes in cytosolic pH had only minimal effects on the sustained [Ca2+]i plateau. The results demonstrate a receptor-mediated Ca2+ entry mechanism, which results in a small increase in [Ca2+]i important in the maintenance of sustained amylase release.

scholarly journals P21-activated kinase 4 in pancreatic acinar cells is activated by numerous gastrointestinal hormones/neurotransmitters and growth factors by novel signaling, and its activation stimulates secretory/growth cascades

2018 ◽  
Vol 315 (2) ◽  
pp. G302-G317 ◽  
Author(s):  
Irene Ramos-Alvarez ◽  
R. T. Jensen
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Gastrointestinal Hormones ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Group Ii ◽  
P21 Activated Kinase ◽  
Signal Cascades

p21-activated kinases (PAKs) are highly conserved serine/threonine protein kinases, which are divided into two groups: group-I (PAKs1–3) and group-II (PAKs4–6). In various tissues, Group-II PAKs play important roles in cytoskeletal dynamics and cell growth as well as neoplastic development/progression. However, little is known about Group-II PAK’s role in a number of physiological events, including their ability to be activated by gastrointestinal (GI) hormones/neurotransmitters/growth factors (GFs). We used rat pancreatic acini to explore the ability of GI hormones/neurotransmitters/GFs to activate Group-II-PAKs and the signaling cascades involved. Only PAK4 was detected in pancreatic acini. PAK4 was activated by endothelin, secretagogues-stimulating phospholipase C (bombesin, CCK-8, and carbachol), by pancreatic GFs (insulin, insulin-like growth factor 1, hepatocyte growth factor, epidermal growth factor, basic fibroblast growth factor, and platelet-derived growth factor), and by postreceptor stimulants (12-O-tetradecanoylphobol-13-acetate and A23187 ). CCK-8 activation of PAK4 required both high- and low-affinity CCK1-receptor state activation. It was reduced by PKC-, Src-, p44/42-, or p38-inhibition but not with phosphatidylinositol 3-kinase-inhibitors and only minimally by thapsigargin. A protein kinase D (PKD)-inhibitor completely inhibited CCK-8-stimulated PKD-activation; however, stimulated PAK4 phosphorylation was only inhibited by 60%, demonstrating that it is both PKD-dependent and PKD-independent. PF-3758309 and LCH-7749944, inhibitors of PAK4, decreased CCK-8-stimulated PAK4 activation but not PAK2 activation. Each inhibited ERK1/2 activation and amylase release induced by CCK-8 or bombesin. These results show that PAK4 has an important role in modulating signal cascades activated by a number of GI hormones/neurotransmitters/GFs that have been shown to mediate both physiological/pathological responses in acinar cells. Therefore, in addition to the extensive studies on PAK4 in pancreatic cancer, PAK4 should also be considered an important signaling molecule for pancreatic acinar physiological responses and, in the future, should be investigated for a possible role in pancreatic acinar pathophysiological responses, such as in pancreatitis. NEW & NOTEWORTHY This study demonstrates that the only Group-II p21-activated kinase (PAK) in rat pancreatic acinar cells is PAK4, and thus differs from islets/pancreatic cancer. Both gastrointestinal hormones/neurotransmitters stimulating PLC and pancreatic growth factors activate PAK4. With cholecystokinin (CCK), activation is PKC-dependent/-independent, requires both CCK1-R affinity states, Src, p42/44, and p38 activation. PAK4 activation is required for CCK-mediated p42/44 activation/amylase release. These results show PAK4 plays an important role in mediating CCK physiological signal cascades and suggest it may be a target in pancreatic acinar diseases besides cancer.

Sign in / Sign up

Export Citation Format

Share Document