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Endocrinology Vol. 141, No. 7 2589-2593
Copyright © 2000 by The Endocrine Society

ARTICLES

Subcellular Distribution of Phospholipase C Isoforms in Rodent Pancreas and Gastric Mucosa1

Shu Wang, Agneta Lukinius, Yinghua Zhou, Peter Stålberg, Anders Gobl, Kjell Oberg and Britt Skogseid

Departments of Medicine Science (S.W., Y.Z., P.S., K.O., A.G., B.S.) and Genetics and Pathology (A.L.), University Hospital, S-751 85 Uppsala, Sweden

Address all correspondence and requests for reprints to: Britt Skogseid, M.D., Ph.D., Department of Medicine, University Hospital, S-751 85 Uppsala, Sweden. E-mail: Britt.Skogseid{at}medsci.uu.se


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Phosphoinositide-specific phospholipase C (PLC) has been implicated as a participant in cell proliferation as well as enzyme and hormone secretion. Defining the subcellular distribution of PLC isoforms would possibly contribute to further understanding of their function. We investigated the intracellular distribution of four PLCs (ß1, ß2, ß3, and {gamma}1) in mouse pancreatic cells as well as mouse and rat gastric mucosa cells by ultrastructural immunocytochemistry. In pancreatic acinar cells, PLCß1 and PLC{gamma}1 were demonstrated in the zymogen granules while PLCß2 was present in the granulae as well as the endoplasmic reticulum (ER), and PLCß3 was prominent in the ER. In the endocrine pancreas, PLCß2 immunolabeling was expressed in the secretory granulae of {alpha}, ß, {delta}, and pancreatic polypeptide cells. PLCß3 showed a slight labeling in the nucleus and ER of all four pancreatic endocrine cell types while PLC{gamma}1 was prominent in {alpha} cell granulae. In the gastric mucosa cells, PLCß2 was highly expressed in the heterochromatin areas and in the ER of parietal, chief, mucous, and enterochromaffin-like cells. PLCß3 were expressed in a manner similar to PLCß2 in those cells; however, no immunoreaction was seen in the ER of parietal cell. PLC{gamma}1 was demonstrated in the chief cell granulae. One possible, although yet speculative, interpretation of our results is that the studied PLC isoforms may be involved in processing in pancreatic secretory granulae and that nuclear PLCß2 and PLCß3 signaling pathways may be operative in the cells of the gastric mucosa.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE MAMMALIAN phospholipases C (PLC) isozymes can be subdivided into three groups, ß, {gamma}, and {delta}. Multiple hormones and growth factors regulate them (1, 2, 3). Many G protein-coupled receptors activate the ß-type isozymes through the {alpha}- and ß{gamma}-subunits of heterotrimeric G proteins (4, 5). Growth factor receptors possessing intrinsic protein tyrosine kinase activity tyrosine phosphorylate the PLC{gamma} isoforms and activate the enzyme (6, 7, 8). Despite some common characteristics, the PLC isozymes mediate multiple different functions. Many studies demonstrate PLC signaling in the nucleus of different cell lines, such as Swiss 3T3 cells and Friend cells (9, 10). The nuclear PLCß1 appears to be increased in mitogenic cell growth in Swiss 3T3 cells (11) and decreased during terminal differentiation in Friend cells (12). Cytosolic PLCß2 appears in the nucleus during HL-60 cell differentiation (13). Yang et al. (14) have reported that the action of PLC may modulate secretion by regulation of Ca2+. An inhibitor of PLC, U73122, reduces inositol triphosphate (IP3) production and regulates hormone secretion in pituitary cells (15, 16). Heterotrimeric G proteins have also been localized to pancreatic zymogen granulae (17). Peptide GPAnt-2a, an antagonist of Gq/11, potentiates calcium-regulated amylase secretion from pancreatic acinus (18). According to Konrad et al. (19), G{alpha}i plays a stimulatory role in mastoparan-induced insulin secretion. Upon stimulation with high concentrations of glucose, insulin release is paralleled by a significant increase in phosphoinositide hydrolysis (20). However, to our knowledge, the localization of PLCs to secretory granulae has not been reported. In the current work, we investigated the subcellular localization of PLC isozymes in the pancreas and gastric mucosa of rodents. We found that PLC isozymes ß1, ß2, ß3, and {gamma}1 display individual subcellular localization patterns that may indicate possible variable functions in secretion and nuclear processes in different cell types.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissue preparation for electron microscopy
Four C57B adult mice and four Sprague Dawley rats (Animal Resources Center B and K, Sollentuna, Sweden) without signs of metabolic or infectious disease were killed. The pancreas and gastric mucosa were immediately cut into 1-mm3 cubes and placed in a fixative consisting of 4% paraformaldehyde/0.5% glutaraldehyde in PBS buffer (pH 7.2) for 2 h at 4 C. After two 15-min washes in PBS, the tissue specimens were dehydrated in 50–95% ethanol while the temperature was progressively decreased from 4 C to -20 C. Infiltration with the hydrophilic low temperature acrylic embedding media, Lowicryl K4M (Agar Scientific (UK) Ltd., Stansted, Essex, UK) overnight at -20 C was followed by polymerization in UV light (360 nm) for 24 h at -20 C, and 48 h at room temperature. Ultrathin sections (50 nm) were mounted on Formvar-coated nickel grids (Sigma, St. Louis, MO).

Immunolabeling
The immunogold labeling was performed as described previously (21). Briefly, the sections were incubated for 30 min at room temperature with 5% normal goat serum, type V (Sigma) in 0.05 M Tris-buffered saline (TBS), pH 7.2, with 0.1% BSA (Sigma). The sections were then incubated with one of the primary antibodies diluted in TBS, pH 7.2, with 0.1% BSA overnight at 4 C. After rinsing in TBS (first pH 7.2, 0.2% BSA and then pH 8.2, 1% BSA) the sections were incubated with goat antirabbit IgG gold-conjugated secondary antibodies diluted 1:20 in TBS, pH 8.2, with 1% BSA at 20 C for 2 h. Finally, contrast staining was performed in uranyl acetate for 20 min and lead citrate for 3.5 min at room temperature before examination in a Philips 201 electron microscope (Philips Technologies, Electronics AB, Stockholm, Sweden).

The intensity of the immunoreactivity of PLCs was estimated by the relative amounts of gold markers in the different organelles. Specific and reproducible labeling in certain organelles was scored as moderately positive immunoreaction (+), and the double or more than double of that amount of gold particles in the same organelles was scored as intense labeling (2+). No immunoactivity with the respective antibodies was denoted negative labeling (-). Negative control sections were incubated without any primary antibody and with homologous nonimmune serum at the same dilutions and conditions as the primary antibodies. Serial sections from each experimental tissue specimen were placed on grids. For each immunogold labeling experiment, grids including sections from the same cells in the various specimen were chosen for the different antibodies as additional antibody specificity controls.

Antibodies
All four primary antibodies were rabbit polyclonal and purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz Biotechnology, Inc., Santa Cruz, CA). The different antibodies are raised against unique sequences of the individual PLC isoforms. Absorption tests for each of the antibodies had been performed by Santa Cruz Biotechnology, Inc. Immunocytochemistry confirmed the specificity of each antibody, and no cross-reactivity occurred. Anti-PLCß1 (G-12) was diluted 1:400, anti-PLCß2 (Q-15) 1:150, anti-PLCß3 (C-20) 1:1200, and anti-PLC{gamma}1 (530) 1:150. Optimal dilution was evaluated by serial dilution test incubation.

As the secondary antibody, we used a polyclonal 15-nm gold-conjugated antirabbit IgG, GAR-G15 (Amersham Pharmacia Biotech, Bucks, UK).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The antibodies to the four PLC isoforms were found to be very specific and the labeling results were reproducible. Only the results of at least four successful labeling experiments were considered. The gold markers were confined to the individual organelles. Nonspecific gold markers and gold markers in the plastic were few. The negative controls included in all labeling experiments were always negative.

Expression of PLCs in mouse pancreatic acinar cells
Immunogold labeling of exocrine pancreatic cells showed a specific subcellular localization of PLCs to the zymogen granules and the endoplasmic reticulum (ER) (Table 1Go). PLCß1 and PLC{gamma}1 were detected solely in the zymogen granulae (Fig. 1Go, a and c) and no labeling was found in the negative controls (see Fig. 4aGo). PLC ß2 was present in the zymogen granulae and in the ER. The immunogold reaction of PLC ß3 was most prominent in the ER, and a low but distinct labeling was detected in the heterochromatin area (Fig. 1bGo). The zymogen granulae material was homogenous in electron density.


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  		Table 1. Subcellular distribution of PLC isoforms in mouse pancreas as assessed by immunogold labeling

 


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  		Figure 1. Top, Subcellular distribution of PLCs in the acinar cells of mouse pancreas by immunogold labeling. a, PLCß1 in pancreatic zymogen granulae (G). b, PLCß3 expression in endoplasmic reticulum (ER). c, PLC{gamma}1 in pancreatic zymogen granulae. N, Nucleus; M, mitochondria. Magnification, x12,000. Bars represent 1 µm.

 


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  		Figure 4. Examples of negative immunolabeling results in mouse pancreatic and rat gastric ECL cells when respective primary antibodies of PLCs were omitted. a, PLCß1 in a mouse acinar cell. b, PLCß2 in secretory granulae of a mouse pancreatic ß-cell. c, PLC{gamma}1 in a mouse endocrine pancreatic {alpha}-cell. d, PLCß3 in a rat ECL cell. No gold markers are found in any of the negative control immunolabeling experiments. ER, Endoplasmic reticulum; G, granula; N, nucleus; M, mitochondria; HC, heterochromatin. Magnification, x36,000. Bars represent 0.5 µm.

 
Expression of PLCs in mouse pancreatic endocrine cells
Glucagon-producing {alpha} cells, insulin-producing ß-cells, somatostatin-producing {delta}-cells, and pancreatic polypeptide (PP)-producing cells were identified with electron microscopy based on the ultrastructural characteristics of their secretory granulae. The {alpha}-cell contains round granulae with an eccentric core of high density surrounded by a less electron-dense halo. The ß-cell possesses round granulae with a crystalline core of medium density and a translucent halo. The {delta}-cell contains round, bigger homogenous granulae of low density. Finally, the PP cell has compact, small, round granulae of medium density (22).

The expression of PLCs in pancreatic endocrine cells was examined only in mouse. PLCß1 immunoreactivities in the endocrine cells of the pancreas were not evident (Fig. 2aGo and Table 1Go). PLC ß2 markers were observed in granulae of {alpha}-, ß-, {delta}-, and PP cells (Fig. 2bGo and Table 1Go). The PLCß2 labeling intensity of ß-cell granulae was higher than that of other cell granulae. No gold marker was present in granulae of the negative controls (Fig. 4bGo). A weak labeling of PLCß3 was present in the endoplasmic reticulum (ER) and nucleus of pancreatic {alpha}-, ß-, {delta}-, and PP cells. PLC{gamma}1 exhibited a distinct labeling in the {alpha}-, ß-, and {delta}- cell granulae (Fig. 2cGo and Table 1Go). The negative controls showed no labeling in the {alpha}-cell granulae (Fig. 4cGo).



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  		Figure 2. Middle, Localization of PLCs in mouse endocrine pancreatic {alpha} and ß cells. a, Pancreatic {alpha} (long arrows) and ß cell (short arrows) secretory granulae are free of PLCß1 labeling. b, PLCß2 immunogold labeling in secretory granulae of a ß-cell. c, PLC{gamma}1 immunolabeling in granulae of an {alpha}-cell. Magnification, x24,000 in panel a, x36,000 in panels b and c. N, Nucleus. Bars represent 0.5 µm.

 
Expression of PLCs in mouse and rat gastric mucosa
Our study reveals the similar subcellular expression patterns of the PLCs in mouse and rat gastric mucosa cells. PLCß2 was highly expressed in the heterochromatin areas in the nuclei and endoplasmic reticulum of chief, parietal, mucous, and enterochromaffin-like (ECL) cells (Table 2Go). PLCß3 immunoreactivity (Fig. 3Go, a and b, and Table 2Go) revealed similar expression patterns as PLCß2 in those cells; however, no immunoreaction was seen in the ER of parietal cell. The negative control showed no labeling of PLCß3 in the heterochromatin areas of rat ECL cells (Fig. 4dGo). PLC{gamma}1 was present in the granulae of chief cells. No PLCß1 labeling of the mucosa cells was found in the two rodent species.


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  		Table 2. Subcellular distribution of PLC isoforms in rodent gastric mucosa cells as assessed by immunogold labeling

 


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  		Figure 3. Bottom, Expression of PLCß3 in rat gastric mucosa cells. The heterochromatin (HC) in the nucleus (N) is intensely labeled in an ECL cell (panel a) and in a parietal cell (panel b). G, Granula; M, mitochondria. Magnification, x36,000 in panel a and x24,000 in panel b. Bars represent 0.5 µm.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this ultrastructural study of mouse and rat gastric mucosa as well as mouse pancreas, the expression patterns of four of the ten known mammalian PLCs were demonstrated. We found that PLCs were present in endocrine and exocrine pancreatic secretory granulae. The receptor-mediated activation of PLC and the consequent production of IP3 as well as diacylglycerol (DAG) are believed to be involved in regulation of secretion (23, 24). The local Ca2+ spikes in the secretory pole of the acinar cells directly trigger exocytotic secretion (25). A recent study has shown that IP3 could modulate release of Ca2+ from the pancreatic zymogen granulae (26). Secretion of insulin also requires an increased intracellular Ca2+ concentration (27, 28). In addition to calcium, it has also been implied that protein kinase C (PKC) isoenzymes contribute to the regulation of hormone secretion from pancreatic cells. Glucose stimulation of rat islet cells results in translocation of PKC from a predominantly cytosolic location to a membrane compartment (29). Inhibition of DAG kinase prevents DAG catabolism and amplifies glucose-induced insulin secretion (30). Our observations suggest that the variable subcellular localization of these four PLCs in different pancreatic granulae may reflect their specific roles in hormone and enzyme secretion. Accordingly, the localization of PLCß2 and PLCß3 in the ER implies a correlation to protein synthesis.

In addition, our study of the mouse and rat gastric mucosa cells provides evidence that PLCß2 and PLCß3 reside in the areas of heterochromatin known for repression of transcription (31). This result is consistent with our previous observation that PLCß3 is localized in heterochromatin areas of mouse neuron (32). PLCß signaling activity has been demonstrated at a nuclear level in Swiss 3T3 and Friend cells (9, 10). Many studies have found that the nuclear activities of PLC are related to DNA synthesis and cell proliferation (11, 33, 34). Transfection of PLCß3 to neuroendocrine tumor cell lines inhibits the cell growth rate and reduces cell proliferation (35). We have also observed that PLCß3-deficient mouse embryos are blocked at about the four-cell stage (36). Hence, expression of PLCß3 may regulate DNA synthesis and cell proliferation. Sun et al. (37) have also reported that nuclear DAG is elevated during the G2 phase, and inhibition of PLC leads to cell cycle arrest in the G2 phase in the HL60 leukemia cell line. Our present localization data indicate that PLCß2 and PLCß3 isozymes may correspond to the suggested nuclear activity of PLC in rodent gastric mucosa cells. However, the specific role of PLCs localized to the nuclei and granulae needs to be assessed.


   Acknowledgments
 
We appreciate the technical assistance of Margareta Halin Lejonklou.


   Footnotes
 
1 This work was supported by grants from The Swedish Cancer Society, The Lions Foundation for Cancer Research, The Swedish Medical Council, The Swedish Medical Society, and The Torsten and Ragnar Ssderbergs Foundation. Back

Received June 28, 1999.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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