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Structural and Secretory Polarity in the Pancreatic Acinar Cell

Amy Chang, James D. Jamieson

10.1002/cphy.cp060327

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 Development of Structural Polarity
1.1 The Developing Pancreas
1.2 Tight Junctions
1.3 Cell‐Substrate Interactions
2 Polarized Secretion in The Pancreas
3 Relationship Between Structural and Functional Polarity
4 Ontogeny of Pancreatic Secretion
5 Distal Events in Stimulus‐Secretion Coupling
5.1 Participation of the Cytoskeleton
5.2 Regulatory Events
5.3 Compensatory Endocytosis
6 Regulated and Constitutive Secretion
7 Biogenesis of Membrane and Secretory Polarity
Figure 1. Figure 1.

Light‐microscopic autoradiography of pancreatic lobules labeled with radiolabeled cholecystokinin (CCK). Pancreatic lobules were incubated in buffer containing 125I‐labeled cholecystokinin triacontatriapeptide (125I‐CCK‐33) for 5 min at 23°C before being fixed and processed for light‐microscopic autoradiography. A: fetal pancreas labeled with 125I‐CCK‐33; B: control preparation of fetal pancreas incubated with radiolabeled CCK and 200‐fold excess unlabeled hormone; C: neonatal pancreas labeled with 125I‐CCK‐33; D: control preparation of neonatal pancreas incubated with radioligand in presence of unlabeled hormone. Arrows, autoradiographic grains localized around the periphery of acinar cells; arrowheads, in B, autoradiographic grains nonspecifically associated with mesenchymal tissue. Bar, 10 μm. Autoradiographic labeling of acinar cells in both fetal and neonatal pancreas is specific (A and C), because a very low level of nonspecific radioactivity is randomly associated with cells when 125I‐CCK‐33 labeling occurs in presence of unlabeled CCK (B and D). Cell surface expression of CCK‐binding sites is similar in fetal and neonatal pancreas, supporting the idea that events distal to hormone binding account for difference in secretory responsiveness at the 2 ages. Structure of acinar cells of fetal and neonatal pancreas is strikingly different. Acinar cells of fetal pancreas are packed with zymogen granules, whereas secretory granules of neonatal pancreas are smaller and restricted to cell apical region.

From Chang and Jamieson 20
Figure 2. Figure 2.

Release of newly synthesized proteins from fetal pancreas in comparison with that of adult pancreas. Pancreatic lobules were pulse labeled with [35S]L‐methionine for 2 min and chased for sequential 30‐min periods, as described in Figure 3. Release of radiolabeled proteins from fetal pancreas, normalized for leakage of lactate dehydrogenase (•), occurs in 2 distinct phases: the 1st phase peaks by 2 h of chase, is complete by 6.5 h, and comprises ∼12% of total incorporated radioactivity; the 2nd phase is not yet maximal at 21 h of chase. In adult gland (Δ), a discrete peak in the 2nd secretory phase is observed at 9–10 h of chase. Because stored population of preformed zymogen granules 26 in adult gland (volume density ∼20%) is small, relative to fetal gland (volume density ∼60%), it is possible that rate of exocytosis of newly formed granules depends on number of preformed granules.

From Arvan and Chang 3; top panel) and Arvan and Castle 2; bottom panel)
Figure 3. Figure 3.

Kinetics of amylase secretion from pancreatic lobules incubated in vitro. Pancreatic lobules were isolated from fetal 1 day before birth), neonatal 1 day after birth), and adult rats and preincubated in oxygenated medium at 37°C. Secretion assay was initiated in fresh medium in presence (○, Δ) or absence (•) of an optimal dose of cholecystokinin COOH‐terminal octapeptide (CCK‐8). Amylase activity was assayed in medium aliquots removed at 30‐min intervals and in tissue homogenized at the end of 2‐h incubation period. Secretion from adult (A), neonatal (B), and fetal (C) pancreas is expressed as percent of total tissue amylase released into medium and is approx. linear with time for up to 2 h. Maximal secretory response from neonatal and adult pancreas occurs in response to 10 nM (Δ) and 1 nM (○) CCK‐8, respectively, and rates of secretion from glands at the 2 ages are comparable. In presence of a range of CCK‐8 doses, there is no significant increase in rate of amylase secretion from fetal pancreas. Rate of CCK‐8‐stimulated secretion from neonatal pancreas (minus resting secretion) at 10 nM CCK‐8 [0.23+L0.03%/min (mean +L SE)] is 8‐fold greater than that from fetal gland at same dose of secretagogue [0.03 +L 0.01%/min (mean +L SE)].
Figure 4. Figure 4.

Nonlinear secretion of newly synthesized proteins from fetal pancreas. Pancreatic lobules were pulse labeled with [36S]L‐methionine for 10 min and chased for sequential 30‐min periods with a complete change of medium at each interval. At the conclusion of experiment, lobules were homogenized and medium samples were cleared of particulates by centrifugation. Aliquots of homogenate and medium were divided for analysis by acid precipitation, sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE), and enzyme assays. A: amylase enzyme activity (○) is released into medium with linear kinetics during sequential and discrete chase intervals, whereas radiolabeled protein (•) is released nonlinearly during same period. B: SDS‐PAGE and fluorography of proteins secreted into the medium during sequential 30‐min chase intervals. Identical amount of unlabeled amylase activity was loaded into each lane. Results indicate that each of major protein species follows roughly same nonlinear kinetic pattern as that observed for overall protein radioactivity in A. Well‐characterized digestive enzymes/proenzymes of pancreatic acinar cell comprise majority of secreted proteins. Lane H, pattern of labeled proteins remaining in tissue at conclusion of experiment, after 3.5 h: tissue still contains >80% of labeled protein, which is nearly exclusively in form of digestive enzymes/proenzymes. C: release of newly synthesized amylase and chymotrypsinogen was quantitated by liquid scintillation counting radioactivity contained within gel bands A and C, respectively, on fluorogram in B. The appearance in medium of amylase was delayed in comparison with that of chymotrypsinogen; this probably reflects asynchronous exit of these proteins from rough endoplasmic reticulum, as previously suggested by Scheele and Tartakoff 107a). D: asynchronous release of amylase and chymotrypsinogen is expressed as a time‐related change in the fraction of total radioactivity secreted during each chase interval.

From Arvan and Chang 3
Figure 5. Figure 5.

Kinetics of autoradiographic labeling of the zymogen secretory pathway in the fetal pancreas. Pancreatic lobules were pulse labeled with [3H]amino acids for 2 min and chased for 18 h with a complete change of medium every 30 min. At 40 min, 1 h, 2 h, 4 h, and 18 h lobules were removed from incubation, fixed, and processed for electron‐microscopic autoradiography. A: pulse‐labeled tissue after 40 min, 2 h (near peak of 1st phase of secretion of newly synthesized protein), and 18 h of chase (during the 2nd phase of secretion) (see Fig. 4. Compartments of the zymogen storage pathway: ER, rough endoplasmic reticulum; GO, Golgi apparatus; IG, immature granule/condensing vacuole; ZG, zymogen granule; N, portion of a cell nucleus; L, acinar lumena. Note that majority of autoradiographic grains overlie immature granules/condensing vacuoles (arrows) after 2 h of chase, and grains are concentrated over ZG after 18 h of chase. Bars, 1 μm. B: quantification of autoradiographic grains over established intermediates in zymogen storage pathway. Sum of grains over these structures is set at 100% at each time point. During chase periods corresponding to 1st phase of secretion (<6.5 h), several compartments in storage pathway contain radiolabel. Labeling of ZG is rising sharply when 1st phase of secretion of newly synthesized proteins is declining 2–6 h). Immature granules/condensing vacuoles are maximally labeled at 2 h of chase. Kinetics of autoradiographic labeling indicates that mature ZG do not serve as origin of 1st secretory phase. Data suggest that immature granules/condensing vacuoles could play such a role.

From Arvan and Chang 3


Figure 1.

Light‐microscopic autoradiography of pancreatic lobules labeled with radiolabeled cholecystokinin (CCK). Pancreatic lobules were incubated in buffer containing 125I‐labeled cholecystokinin triacontatriapeptide (125I‐CCK‐33) for 5 min at 23°C before being fixed and processed for light‐microscopic autoradiography. A: fetal pancreas labeled with 125I‐CCK‐33; B: control preparation of fetal pancreas incubated with radiolabeled CCK and 200‐fold excess unlabeled hormone; C: neonatal pancreas labeled with 125I‐CCK‐33; D: control preparation of neonatal pancreas incubated with radioligand in presence of unlabeled hormone. Arrows, autoradiographic grains localized around the periphery of acinar cells; arrowheads, in B, autoradiographic grains nonspecifically associated with mesenchymal tissue. Bar, 10 μm. Autoradiographic labeling of acinar cells in both fetal and neonatal pancreas is specific (A and C), because a very low level of nonspecific radioactivity is randomly associated with cells when 125I‐CCK‐33 labeling occurs in presence of unlabeled CCK (B and D). Cell surface expression of CCK‐binding sites is similar in fetal and neonatal pancreas, supporting the idea that events distal to hormone binding account for difference in secretory responsiveness at the 2 ages. Structure of acinar cells of fetal and neonatal pancreas is strikingly different. Acinar cells of fetal pancreas are packed with zymogen granules, whereas secretory granules of neonatal pancreas are smaller and restricted to cell apical region.

From Chang and Jamieson 20


Figure 2.

Release of newly synthesized proteins from fetal pancreas in comparison with that of adult pancreas. Pancreatic lobules were pulse labeled with [35S]L‐methionine for 2 min and chased for sequential 30‐min periods, as described in Figure 3. Release of radiolabeled proteins from fetal pancreas, normalized for leakage of lactate dehydrogenase (•), occurs in 2 distinct phases: the 1st phase peaks by 2 h of chase, is complete by 6.5 h, and comprises ∼12% of total incorporated radioactivity; the 2nd phase is not yet maximal at 21 h of chase. In adult gland (Δ), a discrete peak in the 2nd secretory phase is observed at 9–10 h of chase. Because stored population of preformed zymogen granules 26 in adult gland (volume density ∼20%) is small, relative to fetal gland (volume density ∼60%), it is possible that rate of exocytosis of newly formed granules depends on number of preformed granules.

From Arvan and Chang 3; top panel) and Arvan and Castle 2; bottom panel)


Figure 3.

Kinetics of amylase secretion from pancreatic lobules incubated in vitro. Pancreatic lobules were isolated from fetal 1 day before birth), neonatal 1 day after birth), and adult rats and preincubated in oxygenated medium at 37°C. Secretion assay was initiated in fresh medium in presence (○, Δ) or absence (•) of an optimal dose of cholecystokinin COOH‐terminal octapeptide (CCK‐8). Amylase activity was assayed in medium aliquots removed at 30‐min intervals and in tissue homogenized at the end of 2‐h incubation period. Secretion from adult (A), neonatal (B), and fetal (C) pancreas is expressed as percent of total tissue amylase released into medium and is approx. linear with time for up to 2 h. Maximal secretory response from neonatal and adult pancreas occurs in response to 10 nM (Δ) and 1 nM (○) CCK‐8, respectively, and rates of secretion from glands at the 2 ages are comparable. In presence of a range of CCK‐8 doses, there is no significant increase in rate of amylase secretion from fetal pancreas. Rate of CCK‐8‐stimulated secretion from neonatal pancreas (minus resting secretion) at 10 nM CCK‐8 [0.23+L0.03%/min (mean +L SE)] is 8‐fold greater than that from fetal gland at same dose of secretagogue [0.03 +L 0.01%/min (mean +L SE)].



Figure 4.

Nonlinear secretion of newly synthesized proteins from fetal pancreas. Pancreatic lobules were pulse labeled with [36S]L‐methionine for 10 min and chased for sequential 30‐min periods with a complete change of medium at each interval. At the conclusion of experiment, lobules were homogenized and medium samples were cleared of particulates by centrifugation. Aliquots of homogenate and medium were divided for analysis by acid precipitation, sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE), and enzyme assays. A: amylase enzyme activity (○) is released into medium with linear kinetics during sequential and discrete chase intervals, whereas radiolabeled protein (•) is released nonlinearly during same period. B: SDS‐PAGE and fluorography of proteins secreted into the medium during sequential 30‐min chase intervals. Identical amount of unlabeled amylase activity was loaded into each lane. Results indicate that each of major protein species follows roughly same nonlinear kinetic pattern as that observed for overall protein radioactivity in A. Well‐characterized digestive enzymes/proenzymes of pancreatic acinar cell comprise majority of secreted proteins. Lane H, pattern of labeled proteins remaining in tissue at conclusion of experiment, after 3.5 h: tissue still contains >80% of labeled protein, which is nearly exclusively in form of digestive enzymes/proenzymes. C: release of newly synthesized amylase and chymotrypsinogen was quantitated by liquid scintillation counting radioactivity contained within gel bands A and C, respectively, on fluorogram in B. The appearance in medium of amylase was delayed in comparison with that of chymotrypsinogen; this probably reflects asynchronous exit of these proteins from rough endoplasmic reticulum, as previously suggested by Scheele and Tartakoff 107a). D: asynchronous release of amylase and chymotrypsinogen is expressed as a time‐related change in the fraction of total radioactivity secreted during each chase interval.

From Arvan and Chang 3


Figure 5.

Kinetics of autoradiographic labeling of the zymogen secretory pathway in the fetal pancreas. Pancreatic lobules were pulse labeled with [3H]amino acids for 2 min and chased for 18 h with a complete change of medium every 30 min. At 40 min, 1 h, 2 h, 4 h, and 18 h lobules were removed from incubation, fixed, and processed for electron‐microscopic autoradiography. A: pulse‐labeled tissue after 40 min, 2 h (near peak of 1st phase of secretion of newly synthesized protein), and 18 h of chase (during the 2nd phase of secretion) (see Fig. 4. Compartments of the zymogen storage pathway: ER, rough endoplasmic reticulum; GO, Golgi apparatus; IG, immature granule/condensing vacuole; ZG, zymogen granule; N, portion of a cell nucleus; L, acinar lumena. Note that majority of autoradiographic grains overlie immature granules/condensing vacuoles (arrows) after 2 h of chase, and grains are concentrated over ZG after 18 h of chase. Bars, 1 μm. B: quantification of autoradiographic grains over established intermediates in zymogen storage pathway. Sum of grains over these structures is set at 100% at each time point. During chase periods corresponding to 1st phase of secretion (<6.5 h), several compartments in storage pathway contain radiolabel. Labeling of ZG is rising sharply when 1st phase of secretion of newly synthesized proteins is declining 2–6 h). Immature granules/condensing vacuoles are maximally labeled at 2 h of chase. Kinetics of autoradiographic labeling indicates that mature ZG do not serve as origin of 1st secretory phase. Data suggest that immature granules/condensing vacuoles could play such a role.

From Arvan and Chang 3
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Article Title: Structural and Secretory Polarity in the Pancreatic Acinar Cell
 

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Amy Chang, James D. Jamieson. Structural and Secretory Polarity in the Pancreatic Acinar Cell. Compr Physiol 2011, Supplement 18: Handbook of Physiology, The Gastrointestinal System, Salivary, Gastric, Pancreatic, and Hepatobiliary Secretion: 531-547. First published in print 1989. doi: 10.1002/cphy.cp060327