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PubMed1982

Two populations of cells with differing proliferative capacities in atypical acinar cell foci induced by 4-hydroxyaminoquinoline-1-oxide in the rat pancreas.

A single intravenous injection of 4-hydroxyaminoquinoline-1-oxide in male Wistar rats at a dose of 6 mg. per kg. of body weight induced atypical acinar cell foci in 100 per cent of the animals. Atypical acinar cell foci could be classified histologically as basophilic and acidophilic foci and acidophilic nodules. Cells in baseophilic foci were large, contained an irregular nucleus and a markedly basophilic cytoplasm with a few to small number of zymogen granules (zymogen-poor cells). By transmission electron microscopy, these cells showed markedly irregular plasma membranes, a well-developed rough endoplasmic reticulum and a few zymogen granules. Cells in acidophilic foci and nodules contained an intensely eosinophilic granular cytoplasm (zymogen-rich cells) and a large oval to round nucleus. By transmission electron microscopy, the cells showed zymogen-rich cytoplasm and irregular lateral plasma membranes. Mitotic activity was completely absent or very rarely observed in normal pancreas or basophilic foci, in contrast to acidophilic foci and nodules in which a mean value of 2.75 +/- 1.27 per 1000 cells was found. Autoradiography confirmed these differences between the proliferative capacity of cells in basophilic foci (1 +/- 1 labeled nuclei per 1000 cells) and acidophilic foci (23.2 +/- 3.15 labeled nuclei per 100 cells). These studies indicate that 4-hydroxyaminoquinoline-1-oxide induces two types of atypical acinar cell foci with different morphologic features and proliferative capacity.

4-Hydroxyaminoquinoline-1-oxide↗
PubMed1996

Phosphorylation of cholecystokinin receptors expressed on Chinese hamster ovary cells. Similarities and differences relative to native pancreatic acinar cell receptors.

Phosphorylation of G protein-coupled receptors is an established mechanism for desensitization in response to agonist stimulation. We previously reported phosphorylation of the pancreatic acinar cell cholecystokinin (CCK) receptor and the establishment of two-dimensional phosphopeptide mapping of its sites of phosphorylation (Ozcelebi, F., and Miller, L. J. (1995) J. Biol. Chem. 270, 3435-3441). Here, we use similar techniques to map sites of phosphorylation of the same receptor expressed on a stable receptor-bearing Chinese hamster ovary (CHO)-CCKR cell line. Like the native cell, the CHO-CCKR cell receptor was phosphorylated in response to agonist stimulation in a concentration-dependent manner; however, the time course was quite different. CHO-CCKR cell receptor phosphorylation increased progressively to a plateau after 15 min, while in the acinar cell it peaks within 2 min and returns to baseline over this interval. There were distinct qualitative and quantitative differences in the sites of phosphorylation of the two receptor systems. One site previously attributed to action of a staurosporine-insensitive kinase in the acinar cell was absent in the CHO-CCKR cell. Site-directed mutagenesis was utilized to eliminate predicted sites of protein kinase C action, but only two of four such sites affected the phosphopeptide map of this receptor. Chemical and radiochemical sequencing were performed on these and other phosphopeptides which were present in both the CHO-CCKR cells and agonist-stimulated pancreatic acinar cells to provide direct evidence for the phosphorylation sites actually utilized. Thus, these data support the usefulness and limitations of a model cell system in studying receptor phosphorylation and desensitization.

Amino Acid Sequence↗
PubMedDate not supplied

Isoproterenol-induced changes in cell cycle kinetics of parotid gland acinar cells in 8-day-old rats.

Isoproterenol (IPR) was shown to alter some parameters of the parotid gland acinar cell cycle in 8-year-old rats. Although the deoxyribonucleic acid (DNA) synthetic period (S) was decreased and the pre-DNA synthetic (G1) period was lengthened, there were no differences in the total cycle time. There was an increase in the 3H-thymidine labeling index from 35.7 to 50.8% combined with a decrease in the value of the mitotic index from 2.64 to 2.16% after IPR was administered. The results suggest that noncycling (G0) cells may be involved in the normal differentiation of the parotid gland and that IPR alters the transition of acinar cells between the cycling and noncycling state.

Animals↗
PubMed2001

Ca(2+)-regulated nitric oxide generation in rabbit parotid acinar cells.

In rabbit parotid acinar cells, the muscarinic cholinergic agonist methacholine induced an increase in the intracellular Ca(2+) concentration and provoked nitric oxide (NO) generation. Ca(2+)-mobilizing reagents such as thapsigargin and the Ca(2+) ionophore A23187 mimicked the effect of methacholine on NO generation. Methacholine-induced NO generation was inhibited by the removal of extracellular Ca(2+). Immunoblot analysis indicated that the antibody against the neuronal type of nitric oxide synthase (NOS) cross-reacted with NOS in the cytosol of rabbit parotid gland cells. Immunofluorescence testing showed that neuronal NOS is present in the cytosol of acinar cells but less in the ductal cells. NOS was purified approximately 8100-fold from the cytosolic fraction of rabbit parotid glands by chromatography on Sephacryl S-200, DEAE-Sephacel, and 29,59-ADP-Sepharose. The purified NOS was a NADPH- and tetrahydroxybiopterin-dependent enzyme and was activated by Ca(2+) within the physiological range in the presence of calmodulin. These results suggest that NO is generated by the activation of the neuronal type of NOS, which is regulated in rabbit parotid acinar cells by the increase in intracellular Ca(2+) levels induced by the activation of muscarinic receptors.

Animals↗
PubMed2006

Effect of Tetrandrine on LPS-induced NF-kappaB activation in isolated pancreatic acinar cells of rat.

AIM: To investigate the effect of Tetrandrine (Tet) on LPS-induced NF-kappaB activation and cell injury in pancreatic acinar cells and to explore the mechanism of Tetrandrine preventing LPS-induced acinar cell injury. METHODS: Male rat pancreatic acinar cells were isolated by collagenase digestion, then exposed to LPS (10 mg/L), Tet (50 micromol/L, 100 micromol/L) or normal media. At different time point (30 min, 1 h, 4 h, 10 h) after treatment with the agents, cell viability was determined by MTT, the product and nuclear translocation of subunit p65 of NF-kappaB was visualized by immunofluorescence staining and nuclear protein was extracted to perform EMSA which was used to assay the NF-kappaB binding activity. RESULTS: LPS induced cell damage directly in a time dependent manner and Tet attenuated LPS-induced cell damage (50 micromol/L, P < 0.05; 100 micromol/L, P < 0.01). NF-kappaB p65 immunofluorescence staining in cytoplasm increased and began showing its nuclear translocation within 30 min and the peak was shown at 1 h of LPS 10 mg/L treatment. NF-kappaB DNA binding activity showed the same alteration pattern as p65 immunofluorescence staining. In Tet group, the immunofluorescence staining in cytoplasm and nuclear translocation of NF-kappaB were inhibited significantly. CONCLUSION: NF-kappaB activation is an important early event that may contribute to inflammatory responses and cell injury in pancreatic acinar cells. Tet possesses the protective effect on LPS-induced acinar cell injury by inhibiting NF-kappaB activation.

Acute Disease↗
PubMed1996

Cell cycle control in isoproterenol-induced murine salivary acinar cell proliferation.

The eukaryotic cell cycle is a summary of a complex network of signal transduction pathways resulting in both DNA replication and cell division. Cyclin-dependent kinases (CDKs) control the cell cycle in all eukaryotes, whereas other proteins, known as cyclins, act as their regulatory subunits. Chronic injection with isoproterenol (ISO) can induce acinar cell proliferation in rodent salivary glands. Cyclins and CDK proteins from control and ISO-treated murine parotid acinar cells were detected by using Western blotting techniques. By comparing the expression of these cell cycle regulatory kinases in the parotid acinar cell transition from a quiescent state to a hypertrophic state, we found rapid increases in the protein levels of all CDKs, cyclin D and proliferating cell nuclear antigen (PCNA). The highest protein levels for CDKs and cyclins appeared at about 72 hr of ISO stimulation and were coincident with the highest rate of increase in gland wet weight. After 72 hr, the increase of both cell cycle protein and gland wet weight began to subside. By using a co-immunoprecipitation method, the following cell cycle regulators (CDK-cyclin complexes) were detected, CDK4-cyclin D, CDK2-cyclin E, CDK2-cyclin A, and cdc2-cyclin B, along with an increase in kinase activity over control untreated animals. Additionally, we detected significant decreases in the newly isolated CDK inhibitor (CKI) p27kip but not Wee 1 kinase. The increased levels of CKI correlated with a decrease in kinase activity of CDK/cyclin complexes by 144 hr of chronic isoproterenol treatment. Our data suggest that the holoenzymes for cell cycle control (cyclin-CDK complexes) function as a final regulatory mechanism leading to salivary gland acinar cell proliferation. The gradual decline in protein levels of the CDKs and cyclins after 3 days of chronic treatment further indicates that ISO-induced proliferation of parotid acinar cells is self-limiting and non-tumorigenic.

Animals↗
PubMed1991

GTP-sensitivity of the energy-dependent Ca2+ storage pool in permeabilized pancreatic acinar cells.

Isolated rabbit pancreatic acinar cells, permeabilized by saponin treatment and incubated in the presence of 0.1 microM free Ca2+, accumulated 3.3 nmol of Ca2+/mg of acinar protein in an energy-dependent pool. Part of this energy-dependent pool could be released by GTP in a polyethylene glycol-dependent manner. The kinetics of GTP-induced release of Ca2+ showed a biphasic pattern with an initial rapid phase followed by a sustained slower phase. In contrast, IP3-induced release of Ca2+ was completed within 30 s following addition of IP3. No reuptake of Ca2+ was observed following GTP- or IP3-induced release of Ca2+. The GTP effect was independent of IP3 and not inhibited by Ca2+, indicating that the IP3-operated Ca2+ channel is not involved in GTP-induced release of Ca2+. The size of the IP3-releasable pool was not affected by GTP, indicating that GTP, when added to permeabilized acinar cells, does not promote the coupling between IP3-insensitive and IP3-sensitive Ca2+ accumulating organelles. Thus, in permeabilized acinar cells, GTP and IP3 act on different Ca2+ sequestering pools. Interestingly, however, comparison of the size of the GTP-releasable pool with that of the IP3-releasable pool for the cell preparations used in the present study, revealed an inversed relationship, indicating that at the time of permeabilization the GTP-releasable pool can be coupled to a greater or lesser extent to the IP3-releasable pool. This suggests that, in the intact cell, a GTP-dependent mechanism may exist that controls the size of the IP3-releasable pool by coupling IP3-insensitive to IP3-sensitive organelles. Moreover, this suggests that the extent of coupling is preserved during permeabilization.

Animals↗
PubMed1977

Foreign serum-induced pancreatitis in mice. II. Secretory disturbances of acinar cells.

As previously reported, pancreatic acinar cell necrosis and inflammation develop in mice a few hours after one intraperitoneal injection of foreign serum. However, sublethally injured acinar cells exhibited notable increases in both zymogen granule numbers and amylase activity, observed within 3 hours and increasing with time. These two changes were coupled with a progressive decrease in the secretory response to pilocarpine and were preceded by significant disturbances in pancreatic tissue concentrations of sodium and potassium. We conclude that (1) the granule increase results from an induced disturbance of the granule exocytosis mechanism while granule formation continues and, therefore, (2) the granule secretory process is more sensitive to the serum injury mechanism than is the zymogen synthesis process. Although the granule increases developed in acinar cells throughout most of the nonnecrotic gland and persisted for at least 24 hours, acinar cell necrosis was maximal in extent--approximately 25% of the gland in severest form--by 12 to 15 hours. We conclude, therefore, that the increase in granules is neither the primary determinant nor initiator of acinar cell death. The latter is likely caused by disturbed plasma membrane functions, sufficient in some cells to result in lethal changes in ion and fluid composition. The injury mechanism, which permits granule formation to go on in the face of impaired granule exocytosis, is yet to be worked out. The possibilities are discussed in relationship to the reactivity of foreign sera for target cell plasma membranes.

Amylases↗
PubMed1995

Volume-activated chloride channels in rat parotid acinar cells.

1. Rat parotid acinar cells undergo a regulatory volume decrease in response to hypotonically induced cell swelling that is sensitive to K+ and Cl- gradients. To investigate the potential mechanisms involved, the whole-cell patch-clamp technique was used to characterize a volume-sensitive Cl- channel in rat parotid acinar cells. 2. Exposure of cells to a hyposmotic gradient induced large Cl- currents that exhibited outward rectification and were not affected by membrane potential or the absence of intracellular Ca2+. Low external pH increased the currents at all potentials without affecting current kinetics. These currents were nearly abolished when the cells were in hypertonic conditions. This decrease in the current amplitude was correlated with a decrease in the cell size. 3. The volume-sensitive currents displayed little or no time dependence, whereas Ca(2+)-activated Cl- channels, present in the same cells, displayed slow activation kinetics and large, time-dependent tail currents upon repolarization to the holding potential. 4. The reversal potential of the osmotically activated channels was close to the predicted chloride equilibrium potential and was sensitive to the physiological extracellular Cl- concentration ([Cl-]o). The relationship between reversal potential and [Cl-]o was fitted to a modified Nernst equation with a slope of 51 mV per decade, consistent with a Cl- selective conductance. 5. The anion permeability sequence of the channel, obtained from the shifts of the reversal potentials of the volume-sensitive Cl- current, was: SCN- > I- > NO-3 > Br- > Cl- > formate > propionate = methanesulphonate = acetate > or = F- > or = butyrate > valerate > gluconate = glucuronate = glutamate. 6. The current through the volume-sensitive channels was inhibited by the Cl- channel blocker SITS (4-acetamido-4'-isothiocyanatostilbene-2,2'-disulphonic acid) in a voltage-dependent manner. 7. We conclude that rat parotid acinar cells express an outwardly rectifying Cl- current that can be activated by swelling under hypotonic conditions. This Cl- conductance may be an element of the cellular mechanisms of volume regulation in exocrine glands.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1998

Origin of acinar cell regeneration after atrophy of the rat parotid induced by duct obstruction.

Acinar cell regeneration in the rat parotid gland after atrophy induced by a one week period of duct obstruction was examined using histology, immunohistochemistry and transmission electron microscopy (TEM). For immunohistochemistry, antibodies to 5-bromo-2'-deoxyuridine (BrdU), injected one hour before tissue collection, and cytokeratin were employed. When clips were removed from the duct, only ductal epithelial cells remained; all acinar cells had been deleted. Some duct cells were BrdU positive. After three days, newly-formed acini comprising immature acinar cells had appeared; many of the cells were BrdU positive and mitotic figures were readily identified. Thereafter progressive acinar cell maturation and proliferation occurred, parotid gland weight returning to control levels by 7 days. Peak BrdU labelling indices for duct and acinar cells were on days 0 and 4, respectively. By TEM, cytoplasmic organelles in epithelial cells of transitional duct-acinar structures seen at 2 days were poorly developed. Immature acinar cells seen on day 3 contained zymogen granules and had increased endoplasmic reticulum and mitochondria. By day 5, maturing acinar cells had abundant endoplasmic reticulum and zymogen granules, resembling acinar cells in control glands. These observations indicated origin of acinar cell precursors from duct cells during regeneration of the acinar cell-free atrophic gland. Subsequent expansion of the acinar cell population was dependent on maturation and proliferation of these newly-formed cells.

Animals↗
PubMed1997

The endoplasmic reticulum can act as a functional Ca2+ store in all subcellular regions of the pancreatic acinar cell.

Stimulation of pancreatic acinar cells raises [Ca2+]i via Ca2+ release from inositol-1,4,5-trisphosphate (InsP3)-sensitive intracellular Ca2+ stores, generally considered to reside within the endoplasmic reticulum (ER). However, with physiological doses of cholinergic agonists, the [Ca2+]i increase is localized to the apical (secretory) pole of the cell, leading to suggestions that zymogen (secretory) granules themselves may constitute an InsP3-sensitive Ca2+ store responsible for localized Ca2+ release. We have therefore re-investigated whether the ER in pancreatic acinar cells is capable of acting as a functional Ca2+ store in all, or only some, cellular regions. In streptolysin O-permeabilized cells, the ER accumulated up to 25 mmol of 45Ca2+ per liter ER volume by an ATP-dependent, thapsigargin-sensitive, process. This tracer Ca2+ uptake was dependent on ambient (loading) [Ca2+], as was the intra-ER free [Ca2+], assessed by imaging the fluorescence of Magfura-2 within the Ca2+ stores. Comparison of free and total intra-ER [Ca2+] indicated that 200-300 Ca2+ ions are bound within the ER lumen for every Ca2+ ion remaining free. Subcellular analysis showed that ER stores in all regions of the permeabilized cell took up Ca2+ at loading [Ca2+] between 60 nM and 1 microM. Thapsigargin released Ca2+ from stores in all cellular regions, as did InsP3. Immunofluorescence with antibodies against sarco(endo)plasmic reticulum-2b type Ca2+,Mg2+-ATPase or calreticulin confirmed that ER Ca2+ stores were present throughout the cytoplasm. In summary, these results clearly show that the endoplasmic reticulum can act as a functional Ca2+ store in all regions of the acinar cell, including the apical pole.

Animals↗
PubMed1962

Restitution of pancreatic acinar cells following ethionine.

The regeneration of the pancreatic acinar cell was studied at four time periods after ethionine had destroyed most of the acinar cells. Within 2 days of the last ethionine injection, small basophilic cells (pre-acinar cells) with whorls of ergastoplasm or nebenkern were present. These cells also contained a decreased amount of Golgi substance, small zymogen granules, and a fine granularity of the nuclear matrix. They showed persistence of the characteristic ergastoplasm lesion produced by ethionine. Eight days after the last ethionine injection, the nebenkern was replaced by approximately normal appearing ergastoplasm and the nucleoli and Golgi bodies were enlarged. Zymogen granules were less dense but more abundant. Mitochondria were considerably enlarged. Most cells showed no ethionine lesions or only small foci of damage. Eighteen days after the cessation of ethionine, a good approximation of the normal acinar cell was present. The whorls of ergastoplasm appeared at a time (day 12) when basophilia was pronounced. Other studies showed that nucleic acid and protein precursors began to show an increased concentration in acinar cells at this time. The appearance of nebenkern during a phase of cellular recovery and its absence during a phase of replication when mitotic indices were high suggest that its presence is more indicative of ergastoplasmic synthesis than of cell multiplication as such. Possibly the increased density of zymogen granules was a reflection of this increased protein synthesis. The increase in size of Golgi apparatus occurred prior to the replenishment of zymogen granules and thus satisfied a precursor relationship for a possible role in the formation of these secretory structures. Evidence suggests that some injured acinar cells recover from the ethionine and protein-free regimen and give rise to most of the new acinar cells formed. It is possible that, under the severe conditions which prevailed, the centroacinar ductule cells may also have given rise to some acinar cells.

Acinar Cells↗
PubMed2003

Non-uniform distribution of mitochondria in pancreatic acinar cells.

The distribution of mitochondria in pancreatic acinar cells was investigated using confocal fluorescence microscopy and transmission electron microscopy (EM). Acinar cells were studied either after enzymatic isolation or in small segments of undisassociated pancreatic tissue. Loading of isolated acinar cells with Mito Tracker Green or Red, a fluorescence mitochondrial probe, showed that mitochondria are predominantly situated in the perigranular, subplasmalemmal and perinuclear regions. Subsequent applications of EM fixatives induced a leak of the fluorescent indicator to the cytosol but did not change the distribution of mitochondria. EM was then performed on isolated acinar cells and on acinar cells of pancreatic tissue segments. The intracellular distribution of mitochondria was quantified by calculating the percentage of the cross-sectional area that was occupied by mitochondria. In isolated acinar cells the highest density of mitochondria was seen in the perigranular region, where mitochondria occupied 25.69+/-1.58% of the area, then the subplasmalemmal region with 12.61+/-0.77% and the perinuclear region with 9.07+/-0.97% ( n=26). Similar results were obtained from acinar cells of pancreatic tissue segments: the perigranular 22.9+/-1.95%, subplasmalemmal 12.45+/-0.78% and perinuclear regions 9.07+/-0.97% ( n=26). The outer mitochondrial membranes were frequently positioned close to membranes of the ER, which followed the outer contour of mitochondria. Mitochondria were never found in direct contact with the nuclear envelope: there were usually layers of ER between the mitochondrial and nuclear membranes. Subplasmalemmal mitochondria were found in a very close proximity to the plasma membrane with no ER layers between the mitochondrial and the corresponding plasma membranes. We conclude that in pancreatic acinar cells mitochondria are preferentially distributed to perigranular, subplasmalemmal and perinuclear regions and this distribution is not affected by isolation or fixation procedures.

Animals↗
PubMed2002

A role for phosphorylation of inositol 1,4,5-trisphosphate receptors in defining calcium signals induced by Peptide agonists in pancreatic acinar cells.

Stimulation of pancreatic acinar cells with acetylcholine (ACh) and cholecystokinin (CCK) results in an elevation of cytosolic calcium ([Ca(2+)](c)) through activation of inositol 1,4,5-trisphosphate receptors (InsP(3)R). The global temporal pattern of the [Ca(2+)](c) changes produced by ACh or CCK stimulation differs significantly. The hypothesis was tested that CCK stimulation results in a protein kinase A (PKA)-mediated phosphorylation of InsP(3)R and this event contributes to the generation of agonist-specific [Ca(2+)](c) signals. Physiological concentrations of CCK evoked phosphorylation of the type III InsP(3)R, which was blocked by pharmacological inhibition of PKA. Imaging of fura-2-loaded acinar cells revealed that the rate of [Ca(2+)](c) rise during CCK-evoked oscillations slows with each subsequent oscillation, consistent with a developing modulation of release, whereas the kinetics of ACh-evoked oscillations remain constant. Stimulation of cells with ACh following activation of PKA resulted in a slowing of the ACh-evoked [Ca(2+)](c) rise, which now resembled a time-matched CCK response. PKA activation also resulted in a slowing of [Ca(2+)](c) increases elicited by photolysis of caged InsP(3). Targeted, PKA-mediated phosphorylation of type III InsP(3)R is involved in a physiological CCK response, as disruption of the targeting of PKA with the peptide HT31 resulted in marked changes in the CCK-evoked [Ca(2+)](c) signal but had no effect on ACh-evoked responses. Stimulation of cells with bombesin, which evokes [Ca(2+)](c) oscillations indistinguishable from those produced by CCK, also results in PKA-mediated phosphorylation of type III InsP(3)R. Thus, we conclude that PKA-mediated phosphorylation of type III InsP(3)R is a general mechanism by which the patterns of [Ca(2+)](c) oscillations are shaped in pancreatic acinar cells.

Acetylcholine↗
PubMed2000

Allelotype of pancreatic acinar cell carcinoma.

Pancreatic acinar cell carcinoma (PAC) is a rare pancreatic tumor for which no information about chromosomal and gene anomalies is available. We performed genome-wide allelotyping of 9 PACs using DNA from 5 frozen and 4 paraffin-embedded samples and 76 PCR-amplified, chromosome-specific microsatellite markers. High degrees of allelic loss were found, with a mean fractional allelic loss of 0.33. Chromosomes 1p, 4q and 17p showed loss of heterozygosity in >70% of cases and chromosomes 11q, 13q, 15q and 16q, in 60% to 70% of cases. Chromosomes 3q, 6q, 8q, 18q and 21q showed loss in 50% to 60% of cases. All of the remaining chromosomes showed no or few allelic losses. The resulting allelotype of PAC is markedly different from that of either ductal or endocrine tumors of the pancreas, and the involvement of chromosomes 4q and 16q appears to be characteristic of this tumor type. High-resolution mapping of the 12 frequently altered chromosomes in 5 cases with 222 markers permitted subchromosomal localization of regions of consensus loss on 5 chromosomes, including 1p36.31, 3p25.2, 4q26-31.1, 15q15-22.1 and 16q21-q22.1. Our findings suggest that PAC tumorigenesis involves molecular pathways different from those occurring in more common pancreatic tumor types.

Adolescent↗
PubMedDate not supplied

Diverse perturbations may alter the lacrimal acinar cell autoantigenic spectra.

Lacrimal gland acinar cell autoantigens in Sjögren's syndrome include both intracellular proteins and plasma membrane proteins, to which the immune system normally must be tolerant. Attention has largely focused on the roles apoptotic cell death may play in exposing sequestered autoantigens and novel surface epitopes. We hypothesize that perturbations of ongoing membrane traffic in intact, functioning cells may also increase autoantigen exposure. We review the vesicular traffic between acinar cell basal-lateral plasma membranes (blm) and endomembrane compartments, then describe experiments in which isolated acinar cells were stimulated with epidermal growth factor (EGF), lysed, and analyzed by sorbitol gradient centrifugation. Whereas the cholinergic agonist, carbachol, impairs traffic from the trans-Golgi network to prelysosomes, causing Golgi, secretory, and lysosomal proteins to reflux into domains of the trans-Golgi network that communicate with the blm and to accumulate in the blm, EGF specifically causes a 2.6-fold (P < 0.05) increase in the beta-hexosaminidase content of the blm fraction, apparently by impairing traffic from early endosomes to prelysosome. We, therefore, suggest that a variety of physiologic stimuli may alter the spectra of autoantigens acinar cells secrete to the interstitium, express in their blm, and present via MHC Class II molecules after proteolytic processing.

Animals↗
PubMed1993

Control of cholecystokinin receptor dephosphorylation in pancreatic acinar cells.

Phosphorylation of cell surface receptors regulates the physiological response to many hormones and neurotransmitters. We have demonstrated that the receptor for cholecystokinin (CCK), the major secretagogue for the exocrine pancreas, is phosphorylated on serines in response to CCK (Klueppelberg, U.G., Gates, L.K., Gorelick, F.S., and Miller, L.J. (1991) J. Biol. Chem. 266, 2403-2408). Receptor phosphorylation was transient, even in the continued presence of agonist, and suggested a role for pancreatic protein phosphatases (PP) in regulating receptor phosphorylation in the intact cell. Treatment of acinar cells with okadaic acid increased the extent and duration of receptor phosphorylation induced by CCK. Receptor phosphorylated in the intact cell in response to CCK was used as substrate to analyze protein phosphatases in pancreatic acinar cell extracts. The predominant CCK receptor phosphatase activity was found in the cytosol and was potently inhibited by okadaic acid (IC50 = 0.2 nM). This phosphatase activity was unaffected by inhibitor-2, Ca2+, or Mg2+, suggesting that the major receptor phosphatase was PP-2A. Stimulation of cells with CCK resulted in a 3-fold increase in protein phosphatase activity toward the CCK receptor, at the same time that phosphorylase a phosphatase activity was unchanged. This increase in receptor phosphatase activity was reflected only in the cytosol, with the particulate activity unchanged. Consistent with this subcellular localization, the hormone-regulated receptor phosphatase activity was PP-2A, with chromatographic separation demonstrating activity in both PP-2A1 and PP-2A2 forms. These data suggest that CCK coordinates the activity of both protein kinases and phosphatases acting on the CCK receptor to control the extent and duration of receptor phosphorylation in the pancreatic acinar cell.

Animals↗
PubMed1984

DNA content of hyperplastic and neoplastic acinar cell lesions in rat and human pancreas.

Pancreatic acinar cell hyperplastic lesions and neoplasms in rats and humans were studied for their nuclear DNA content by microspectrophotometry. Atypical hyperplastic acinar cell lesions induced in rats by azaserine displayed a wide range of DNA contents, 1.5-8C for those composed of acidophilic-type cells and 1.5-9C for those of basophilic-type cells compared with the euploid pattern of 1.5-5C in acinar cells in normal pancreas. The modal DNA values of rat acinar cell adenomas were distributed over an even wider range of 2-11C. In human pancreas, hyperplastic acinar cell lesions composed of eosinophilic-type cells displayed a slightly wider range of DNA content (1.5-8C) than that in surrounding normal acinar cells (1.5-5C). The DNA histograms of basophilic acinar cell lesions were of an aneuploid pattern (2-12C) similar to that of an acinar cell carcinoma (2-15C). These findings demonstrate that acinar cell hyperplastic lesions in rats and humans have an altered genetic complement and suggest that they probably are precursor lesions for acinar cell neoplasms.

Adenoma↗