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Cellular Compartmentation and Protein Processing in the Exocrine Pancreas

George A. Scheele, Horst F. Kern

10.1002/cphy.cp060324

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 Translocation of Proteins Across The Rer Membrane
2 Translocation Receptors
3 Asymmetric Integration of Membrane Proteins Into The Lipid Bilayer
4 Intracisternal Processing and Cellular Sorting of Proteins
4.1 Covalent Intracisternal Processing
4.2 Golgi Compartmentation
4.3 Molecular Sorting of Proteins
4.4 Importance of Cisternal pH in the Cellular Sorting of Proteins
4.5 Intracisternal Transport and Processing of Secretory Proteins
Figure 1. Figure 1.

Comparison of fine structure of an acinar and intralobular duct cell in human pancreas. In the acinar cell, membrane‐bound compartments are distributed in a polar fashion with the rough endoplasmic reticulum (RER) located in the infra‐ and paranuclear regions (N, tangential section of nucleus); Golgi complex (G) and zymogen granules are located in the apical part of the cell. Cytoplasmic compartmentation is less elaborate in the adjacent duct cell, which largely contains free polysomes and minimal RER elements. L, luminal space. Arrows near the basal surface of the acinar cell point to a nerve ending. × 7,000.
Figure 2. Figure 2.

Biochemical events believed to be involved in translocation of secretory proteins across (A) and integration of membrane proteins into (B) the RER membrane. 1, Initiation of protein synthesis begins at the AUG initiation codon either on free ribosomes or ribosomes indirectly attached to the microsomal membrane via the mRNA strand. 2, Following the AUG initiation codon, mRNAs for secretory proteins contain a characteristic set of codons (xxx) that result in translation of the signal‐translocation sequence containing a core region ( rich in hydrophobic amino acids, particularly those with large side chains, Phe, Leu, Ile, Val. Messenger RNAs for nonsecretory proteins do not contain this sequence of codons. 3, The signal peptide when emerged from the channel in the large ribosomal subunit binds to the signal‐recognition particle (SRP; v). 4, Formation of a functional ribosome‐membrane junction: interaction of SRP with the docking protein associated with the RER membrane ( allows polypeptide chain translocation across the membrane to proceed. Formation of a functional ribosome‐membrane junction also involves binding of ribosomes to ribophorins I and II located in the RER membrane (. The mechanism by which the signal peptide is inserted into the membrane is unknown. 5 and 6, Transfer of the polypeptide chain to the cisternal space of the RER. 7, Prior to chain termination, the signal peptide is cleaved from the nascent protein by a protease ( associated with the cisternal leaflet of the RER membrane. The fate of the signal peptide after cleavage is unknown. 8, In the absence of a stop‐transport sequence, chain termination occurs and the completed polypeptide is released to the intravesicular space. Synthesis and translocation of the nascent protein is now complete. The small ribosomal subunit and the mRNA dissociate from the large ribosomal subunit, which remains attached to the membrane for a short time through electrostatic linkages and then is released. B: when a stop‐transport sequence follows the start‐transport signal, the nascent protein remains associated with the lipid bilayer in a transmembrane configuration, as depicted in steps 6', 7', and 8'. When the signal‐transport sequence is not cleaved, the nascent polypeptide chain may also remain associated with the membrane, as depicted in Fig. 4B1.

From Scheele 105
Figure 3. Figure 3.

Schematic comparison of start‐translocation (A) and stop‐translocation (B) peptide signals. Sequences are lined up at the interface between hydrophilic and hydrophobic domains. Hydrophilic domains contain charged residues shown with the appropriate sign enclosed by a circle and partially charged NH2‐terminal residues. Continuous horizontal lines represent hydrophobic domains. Vertical lines (top of each panel) indicate intervals of 5 amino acid residues. Numbers introducing stop‐transport sequences indicate the internal position of these signals (residues from NH2 terminus). Right column, proteins from which peptide signals were taken. Sequences were selected from the literature as follows: anionic pretrypsinogen 87, preproalbumin 116, pre K casein 70, preproparathyroid hormone 42, pregrowth hormone 114, histocompatibility antigen B7 88, glycophorin A 125, Semliki forest virus protein E1 35, membrane‐bound form of IgM μ‐chain 92, and avian sarcoma virus glycoprotein 22.

From Scheele 105
Figure 4. Figure 4.

Asymmetric insertion of membrane proteins. A: potential structures of secretory (A1) and membrane (A2–4) proteins derived after proteolytic cleavage of the start‐translocation signal sequence. B: potential structures of membrane proteins derived in the absence of cleavage of the initial start signal. Ribosomes containing nascent polypeptide chains in the process of loop insertion and chain translocation are shown for reference to topological relationships and biogenetic mechanisms. NH2 and COOH termini are shown in relationship to cytosolic (endoplasmic) and cisternal (exoplasmic) compartments. , Hydrophobic amino acid residues in start‐transport and stop‐transport signal sequences. +, High‐density regions of basic residues, which in combination with preceding hydrophobic sequences constitute stop‐translocation signals. Thermodynamic considerations predict that hydrophobic portions of stop‐transport sequences exist in helical configurations within the lipid bilayer. Configurations of start‐transport sequences in the lipid bilayer are unknown and depend on whether such sequences interact with integral transmembrane proteins.

From Scheele 105
Figure 5. Figure 5.

Formation of glycoproteins through the attachment of N‐linked oligosaccharides. Oligosaccharides of this type occur in 2 general forms, high mannose and complex. Although differing in their final structure, these 2 oligosaccharides have a common biosynthetic origin, being derived from a lipid‐linked oligosaccharide precursor. The lipid carrier is a dolichopyrophosphate (Dol‐P‐P), the lipid moiety of which contains an α‐saturated polyisoprenoid moiety containing 20 isoprene units (together constituting an 80‐carbon chain with branched methyl groups and 20 unsaturated bonds). A: Dol‐P is synthesized in the outer mitochondrial membrane and, by an unknown mechanism, is transferred to the RER membrane. Oligosaccharide precursor is first assembled onto the Dol‐P by enzymes believed to reside on the cytosolic leaflet of the RER membrane (step 1). Assembly involves attachment of 2 N‐acetylglucosamine (GlcNAc), 9 mannose (Man), and 3 glucose (Glc) residues. Linkage patterns vary in a highly specific and reproducible manner. By an unknown mechanism, the Dol‐P‐P‐oligosaccharide precursor then flips in the membrane bilayer, transferring the oligosaccharide to the cisternal surface of the RER (step 2). After transfer of the oligosaccharyl precursor to the protein acceptor (step 3), 3 glucosyl residues are removed by glucosidases I and II, which reside as integral membrane proteins at the cisternal surface of the rough and smooth endoplasmic reticulum (step 4). B: further processing of oligosaccharide chains occurs in the Golgi complex along divergent pathways. Within cis‐Golgi elements, oligosaccharides attached to lysosomal enzymes are phosphorylated at position 6 (step 4a) by a modification process involving the activity of 2 enzymes, GlcNAc‐1‐phosphotransferase and phosphodiester glycosidase. Within mid‐ and trans‐Golgi elements, glycoproteins proceed along a pathway that results in formation of a diverse array of complex oligosaccharides. This latter pathway begins with the removal of mannosyl residues from unbranched saccharides (mannosidase I; step 5). An addition of a GlcNAc residue (step 6) signals the further removal of mannosyl residues from branched saccharides (step 7). Then begins the progressive addition of GlcNAc, galactose (Gal), sialic acid, and fucose (Fuc) residues in a variety of combinations, several of which are depicted in steps 8a–d. GlcNAc and Gal form the core of these terminal additions. Heterogeneity is generated in the number of branch points (biantennary, step 8a; triantennary, step 8b), the fucose addition to the proximal GlcNAc residue, and the type of residue that terminates the oligosaccharide chain (sialic acid or fucose, in a mutually exclusive manner). Repeating disaccharides of the Gal‐β‐1,4‐GlcNAc and GlcNAc‐β‐1,3‐Gal types give rise to erythroglycan, a recently discovered proteoglycan associated with the erythrocyte plasma membrane and to a lesser extent with plasma membranes of other cells. Consistent with these cell biological concepts, glycoproteins associated exclusively with the RER contain only the high‐mannose oligosaccharide.

Adapted from Hubbard and Ivatt 47 and Scheele 105
Figure 6. Figure 6.

Electron micrographs (A and B) and schematic drawing (C) of apical compartments in the pancreatic acinar cell. Rough endoplasmic reticulum (RER), Golgi, and granules are organized in polarized fashion. RER contains membrane‐bound ribosomes and shows transitional elements from which bud smooth‐surfaced vesicles (B). The Golgi complex is composed of 3–4 flattened cisternae in stacked array. Numerous 60‐ to 80‐nm vesicles are concentrated on the cis face and at the lateral rims of the Golgi complex. Some vesicles reveal projections on the outer surface of the membrane (coated vesicles indicated by arrows in B). The Golgi complex serves as a central membrane compartment to which secretory, lysosomal, and membrane proteins are transported for further processing and targeting to their final destinations. The dominant pathway of protein processing and sorting in the acinar cell is represented by the storage, in granule form, and by the release of large quantities of digestive (pro)enzymes into the extracellular ductular space mediated through a secretagogue‐regulated exocytotic pathway (A). Membrane material is recycled (arrows in A) to a large extent to the Golgi complex, where it may be utilized again for the secretory process. Membrane vesicles derived from various types of endocytosis are directed to prelysosomal and lysosomal compartments largely for utilization and/or digestion of receptor‐recruited ligands from the cellular environment. Thus the numerous vesicles observed around the Golgi complex may constitute a variety of functional subgroups involved in a number of transport processes: a) transport of secretory, lysosomal, and membrane proteins from RER to Golgi; b) transport of lysosomal (pro)enzymes to (pre)lysosomal compartments; c) inter‐Golgi transport; d) targeting of membrane proteins to polar surfaces of the cell; and e) internalization of membrane domains from the cell surface. These cellular pathways are schematically depicted in C. CV, condensing vacuole; EX, exocytosis; LYS, lysosome; ZG, zymogen granule. A: X 44,000; B: × 29,000.
Figure 7. Figure 7.

A: kinetics of in vitro discharge of pulse‐labeled proteins from rat pancreatic lobules prepared from control animals (•) and animals infused with 0.25 μg · kg‐1 · h‐1 caerulein for 24 h (▪). Values are expressed as percentage of total content released at each time point studied over 45 min. Minimal transit time is 30 min in control animals and 10 min in stimulated animals. B: autoradiographic demonstration of pancreatic proteins pulse‐labeled for 3 min and chased for 7 min in lobules from an animal stimulated for 24 h, as in A. Autoradiographic grains appear over Golgi cisternae (G), condensing vacuoles, and granules in proximity to the acinar lumen (L). At the same time period in the absence of in vivo hormone stimulation, the majority of grains appear over elements of the RER. X 9,000.

A adapted from Bieger et al. 10
Figure 8. Figure 8.

Redirection of the final step in the secretory pathway during supraoptimal secretagogue stimulation. Under normal conditions (basal and stimulatory) exocytosis occurs exclusively at the luminal plasma membrane as depicted by the micrograph (A), where pancreatic lobules were fixed after stimulation for 15 min with optimal concentrations of caerulein 10‐9 M). Functional activity at the luminal membrane is indicated by the exocytotic image (arrow) and by the presence of numerous coated pits and vesicles (arrowheads) at or near the membrane surface, respectively. Under conditions of supramaximal stimulation for 15 min with 10‐7 M caerulein (B), exocytotic images are absent at the luminal membrane but appear in limited numbers at the lateral plasma membrane (opposing arrows), X 25,000.

Adapted from Scheele et al. 106
Figure 9. Figure 9.

Kinetics of discharge of 7 secretory proteins from guinea pig pancreatic lobules incubated in the presence and absence of 10‐5 M carbachol (A) and 10‐9 M caerulein (B). In a first experiment, discharge of amylase (○) was compared with discharges of chymotrypsinogen (▵), trypsinogen (▿), procarboxypeptidase A (, and procarboxypeptidase B (. In a second experiment, discharge of amylase ( was compared with that of lipase ( and ribonuclease (. Results are expressed as percentage of enzyme activities released into the medium at each time point relative to the sum of activities retained in tissue and discharged into medium at the end of the incubation period. Values given for the 4 zymogens represent corresponding enzyme activities assayed after enzyme activation. Data are normalized to stimulated values at 2 h. Under these conditions the 7 enzymes were discharged in synchrony and in constant proportions during control or secretagogue stimulation. Enzyme activities reflect equilibrium conditions in the cell. Consequently the asynchrony, which occurs during the intracellular transport of exocrine proteins and reflects the nonequilibrium conditions associated with a pulse‐chase protocol, is not observed. Similar findings of parallel discharge of exocrine enzymes have been recently observed under a variety of dietary and hormonal conditions in vivo in the unanesthetized rat 51,52.

From Scheele and Palade 111


Figure 1.

Comparison of fine structure of an acinar and intralobular duct cell in human pancreas. In the acinar cell, membrane‐bound compartments are distributed in a polar fashion with the rough endoplasmic reticulum (RER) located in the infra‐ and paranuclear regions (N, tangential section of nucleus); Golgi complex (G) and zymogen granules are located in the apical part of the cell. Cytoplasmic compartmentation is less elaborate in the adjacent duct cell, which largely contains free polysomes and minimal RER elements. L, luminal space. Arrows near the basal surface of the acinar cell point to a nerve ending. × 7,000.



Figure 2.

Biochemical events believed to be involved in translocation of secretory proteins across (A) and integration of membrane proteins into (B) the RER membrane. 1, Initiation of protein synthesis begins at the AUG initiation codon either on free ribosomes or ribosomes indirectly attached to the microsomal membrane via the mRNA strand. 2, Following the AUG initiation codon, mRNAs for secretory proteins contain a characteristic set of codons (xxx) that result in translation of the signal‐translocation sequence containing a core region ( rich in hydrophobic amino acids, particularly those with large side chains, Phe, Leu, Ile, Val. Messenger RNAs for nonsecretory proteins do not contain this sequence of codons. 3, The signal peptide when emerged from the channel in the large ribosomal subunit binds to the signal‐recognition particle (SRP; v). 4, Formation of a functional ribosome‐membrane junction: interaction of SRP with the docking protein associated with the RER membrane ( allows polypeptide chain translocation across the membrane to proceed. Formation of a functional ribosome‐membrane junction also involves binding of ribosomes to ribophorins I and II located in the RER membrane (. The mechanism by which the signal peptide is inserted into the membrane is unknown. 5 and 6, Transfer of the polypeptide chain to the cisternal space of the RER. 7, Prior to chain termination, the signal peptide is cleaved from the nascent protein by a protease ( associated with the cisternal leaflet of the RER membrane. The fate of the signal peptide after cleavage is unknown. 8, In the absence of a stop‐transport sequence, chain termination occurs and the completed polypeptide is released to the intravesicular space. Synthesis and translocation of the nascent protein is now complete. The small ribosomal subunit and the mRNA dissociate from the large ribosomal subunit, which remains attached to the membrane for a short time through electrostatic linkages and then is released. B: when a stop‐transport sequence follows the start‐transport signal, the nascent protein remains associated with the lipid bilayer in a transmembrane configuration, as depicted in steps 6', 7', and 8'. When the signal‐transport sequence is not cleaved, the nascent polypeptide chain may also remain associated with the membrane, as depicted in Fig. 4B1.

From Scheele 105


Figure 3.

Schematic comparison of start‐translocation (A) and stop‐translocation (B) peptide signals. Sequences are lined up at the interface between hydrophilic and hydrophobic domains. Hydrophilic domains contain charged residues shown with the appropriate sign enclosed by a circle and partially charged NH2‐terminal residues. Continuous horizontal lines represent hydrophobic domains. Vertical lines (top of each panel) indicate intervals of 5 amino acid residues. Numbers introducing stop‐transport sequences indicate the internal position of these signals (residues from NH2 terminus). Right column, proteins from which peptide signals were taken. Sequences were selected from the literature as follows: anionic pretrypsinogen 87, preproalbumin 116, pre K casein 70, preproparathyroid hormone 42, pregrowth hormone 114, histocompatibility antigen B7 88, glycophorin A 125, Semliki forest virus protein E1 35, membrane‐bound form of IgM μ‐chain 92, and avian sarcoma virus glycoprotein 22.

From Scheele 105


Figure 4.

Asymmetric insertion of membrane proteins. A: potential structures of secretory (A1) and membrane (A2–4) proteins derived after proteolytic cleavage of the start‐translocation signal sequence. B: potential structures of membrane proteins derived in the absence of cleavage of the initial start signal. Ribosomes containing nascent polypeptide chains in the process of loop insertion and chain translocation are shown for reference to topological relationships and biogenetic mechanisms. NH2 and COOH termini are shown in relationship to cytosolic (endoplasmic) and cisternal (exoplasmic) compartments. , Hydrophobic amino acid residues in start‐transport and stop‐transport signal sequences. +, High‐density regions of basic residues, which in combination with preceding hydrophobic sequences constitute stop‐translocation signals. Thermodynamic considerations predict that hydrophobic portions of stop‐transport sequences exist in helical configurations within the lipid bilayer. Configurations of start‐transport sequences in the lipid bilayer are unknown and depend on whether such sequences interact with integral transmembrane proteins.

From Scheele 105


Figure 5.

Formation of glycoproteins through the attachment of N‐linked oligosaccharides. Oligosaccharides of this type occur in 2 general forms, high mannose and complex. Although differing in their final structure, these 2 oligosaccharides have a common biosynthetic origin, being derived from a lipid‐linked oligosaccharide precursor. The lipid carrier is a dolichopyrophosphate (Dol‐P‐P), the lipid moiety of which contains an α‐saturated polyisoprenoid moiety containing 20 isoprene units (together constituting an 80‐carbon chain with branched methyl groups and 20 unsaturated bonds). A: Dol‐P is synthesized in the outer mitochondrial membrane and, by an unknown mechanism, is transferred to the RER membrane. Oligosaccharide precursor is first assembled onto the Dol‐P by enzymes believed to reside on the cytosolic leaflet of the RER membrane (step 1). Assembly involves attachment of 2 N‐acetylglucosamine (GlcNAc), 9 mannose (Man), and 3 glucose (Glc) residues. Linkage patterns vary in a highly specific and reproducible manner. By an unknown mechanism, the Dol‐P‐P‐oligosaccharide precursor then flips in the membrane bilayer, transferring the oligosaccharide to the cisternal surface of the RER (step 2). After transfer of the oligosaccharyl precursor to the protein acceptor (step 3), 3 glucosyl residues are removed by glucosidases I and II, which reside as integral membrane proteins at the cisternal surface of the rough and smooth endoplasmic reticulum (step 4). B: further processing of oligosaccharide chains occurs in the Golgi complex along divergent pathways. Within cis‐Golgi elements, oligosaccharides attached to lysosomal enzymes are phosphorylated at position 6 (step 4a) by a modification process involving the activity of 2 enzymes, GlcNAc‐1‐phosphotransferase and phosphodiester glycosidase. Within mid‐ and trans‐Golgi elements, glycoproteins proceed along a pathway that results in formation of a diverse array of complex oligosaccharides. This latter pathway begins with the removal of mannosyl residues from unbranched saccharides (mannosidase I; step 5). An addition of a GlcNAc residue (step 6) signals the further removal of mannosyl residues from branched saccharides (step 7). Then begins the progressive addition of GlcNAc, galactose (Gal), sialic acid, and fucose (Fuc) residues in a variety of combinations, several of which are depicted in steps 8a–d. GlcNAc and Gal form the core of these terminal additions. Heterogeneity is generated in the number of branch points (biantennary, step 8a; triantennary, step 8b), the fucose addition to the proximal GlcNAc residue, and the type of residue that terminates the oligosaccharide chain (sialic acid or fucose, in a mutually exclusive manner). Repeating disaccharides of the Gal‐β‐1,4‐GlcNAc and GlcNAc‐β‐1,3‐Gal types give rise to erythroglycan, a recently discovered proteoglycan associated with the erythrocyte plasma membrane and to a lesser extent with plasma membranes of other cells. Consistent with these cell biological concepts, glycoproteins associated exclusively with the RER contain only the high‐mannose oligosaccharide.

Adapted from Hubbard and Ivatt 47 and Scheele 105


Figure 6.

Electron micrographs (A and B) and schematic drawing (C) of apical compartments in the pancreatic acinar cell. Rough endoplasmic reticulum (RER), Golgi, and granules are organized in polarized fashion. RER contains membrane‐bound ribosomes and shows transitional elements from which bud smooth‐surfaced vesicles (B). The Golgi complex is composed of 3–4 flattened cisternae in stacked array. Numerous 60‐ to 80‐nm vesicles are concentrated on the cis face and at the lateral rims of the Golgi complex. Some vesicles reveal projections on the outer surface of the membrane (coated vesicles indicated by arrows in B). The Golgi complex serves as a central membrane compartment to which secretory, lysosomal, and membrane proteins are transported for further processing and targeting to their final destinations. The dominant pathway of protein processing and sorting in the acinar cell is represented by the storage, in granule form, and by the release of large quantities of digestive (pro)enzymes into the extracellular ductular space mediated through a secretagogue‐regulated exocytotic pathway (A). Membrane material is recycled (arrows in A) to a large extent to the Golgi complex, where it may be utilized again for the secretory process. Membrane vesicles derived from various types of endocytosis are directed to prelysosomal and lysosomal compartments largely for utilization and/or digestion of receptor‐recruited ligands from the cellular environment. Thus the numerous vesicles observed around the Golgi complex may constitute a variety of functional subgroups involved in a number of transport processes: a) transport of secretory, lysosomal, and membrane proteins from RER to Golgi; b) transport of lysosomal (pro)enzymes to (pre)lysosomal compartments; c) inter‐Golgi transport; d) targeting of membrane proteins to polar surfaces of the cell; and e) internalization of membrane domains from the cell surface. These cellular pathways are schematically depicted in C. CV, condensing vacuole; EX, exocytosis; LYS, lysosome; ZG, zymogen granule. A: X 44,000; B: × 29,000.



Figure 7.

A: kinetics of in vitro discharge of pulse‐labeled proteins from rat pancreatic lobules prepared from control animals (•) and animals infused with 0.25 μg · kg‐1 · h‐1 caerulein for 24 h (▪). Values are expressed as percentage of total content released at each time point studied over 45 min. Minimal transit time is 30 min in control animals and 10 min in stimulated animals. B: autoradiographic demonstration of pancreatic proteins pulse‐labeled for 3 min and chased for 7 min in lobules from an animal stimulated for 24 h, as in A. Autoradiographic grains appear over Golgi cisternae (G), condensing vacuoles, and granules in proximity to the acinar lumen (L). At the same time period in the absence of in vivo hormone stimulation, the majority of grains appear over elements of the RER. X 9,000.

A adapted from Bieger et al. 10


Figure 8.

Redirection of the final step in the secretory pathway during supraoptimal secretagogue stimulation. Under normal conditions (basal and stimulatory) exocytosis occurs exclusively at the luminal plasma membrane as depicted by the micrograph (A), where pancreatic lobules were fixed after stimulation for 15 min with optimal concentrations of caerulein 10‐9 M). Functional activity at the luminal membrane is indicated by the exocytotic image (arrow) and by the presence of numerous coated pits and vesicles (arrowheads) at or near the membrane surface, respectively. Under conditions of supramaximal stimulation for 15 min with 10‐7 M caerulein (B), exocytotic images are absent at the luminal membrane but appear in limited numbers at the lateral plasma membrane (opposing arrows), X 25,000.

Adapted from Scheele et al. 106


Figure 9.

Kinetics of discharge of 7 secretory proteins from guinea pig pancreatic lobules incubated in the presence and absence of 10‐5 M carbachol (A) and 10‐9 M caerulein (B). In a first experiment, discharge of amylase (○) was compared with discharges of chymotrypsinogen (▵), trypsinogen (▿), procarboxypeptidase A (, and procarboxypeptidase B (. In a second experiment, discharge of amylase ( was compared with that of lipase ( and ribonuclease (. Results are expressed as percentage of enzyme activities released into the medium at each time point relative to the sum of activities retained in tissue and discharged into medium at the end of the incubation period. Values given for the 4 zymogens represent corresponding enzyme activities assayed after enzyme activation. Data are normalized to stimulated values at 2 h. Under these conditions the 7 enzymes were discharged in synchrony and in constant proportions during control or secretagogue stimulation. Enzyme activities reflect equilibrium conditions in the cell. Consequently the asynchrony, which occurs during the intracellular transport of exocrine proteins and reflects the nonequilibrium conditions associated with a pulse‐chase protocol, is not observed. Similar findings of parallel discharge of exocrine enzymes have been recently observed under a variety of dietary and hormonal conditions in vivo in the unanesthetized rat 51,52.

From Scheele and Palade 111
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Article Title: Cellular Compartmentation and Protein Processing in the Exocrine Pancreas
 

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George A. Scheele, Horst F. Kern. Cellular Compartmentation and Protein Processing in the Exocrine Pancreas. Compr Physiol 2011, Supplement 18: Handbook of Physiology, The Gastrointestinal System, Salivary, Gastric, Pancreatic, and Hepatobiliary Secretion: 477-498. First published in print 1989. doi: 10.1002/cphy.cp060324