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Endocrinology Vol. 140, No. 12 5524-5529
Copyright © 1999 by The Endocrine Society

ARTICLES

Ca2+ Signaling in Mouse Pancreatic Polypeptide Cells1

Yi-Jia Liu2, Bo Hellman and Erik Gylfe

Department of Medical Cell Biology, Uppsala University, SE-751 23 Uppsala, Sweden

Address all correspondence and requests for reprints to: Erik Gylfe, Department of Medical Cell Biology, Biomedicum, Box 571, SE-751 23 Uppsala, Sweden. E-mail: erik.gylfe{at}medcellbiol.uu.se


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Ca2+signaling was studied in pancreatic polypeptide (PP)-secreting cells isolated from mouse islets of Langerhans. After measuring the cytoplasmic Ca2+ concentration ([Ca2+]i), the cells were identified by immunocytochemistry. Most PP-cells reacted to carbachol and epinephrine with prompt and reversible elevation of [Ca2+]i, often manifested as slow oscillations. The carbachol effect was muscarinic, because it was inhibited by atropine. ß-adrenergic elevation of cAMP explains the epinephrine stimulation, which was mimicked by an activator of adenylate cyclase and blocked by an inhibitor of protein kinase A. The responses to carbachol and epinephrine apparently involve depolarization with opening of voltage-dependent Ca2+ channels, because the effects were prevented by the Ca2+ channel antagonist methoxyverapamil and by diazoxide, which activates ATP-dependent K+ (KATP) channels. Being equipped with KATP channels, the PP-cells often responded to tolbutamide or high concentrations of glucose with elevation of [Ca2+]i. Somatostatin reversed the [Ca2+]i elevation obtained by carbachol, epinephrine, tolbutamide, and glucose. These preliminary studies support the idea that glucose has a direct stimulatory effect on the PP-cells, which can be masked by locally released somatostatin. Expressing both KATP channels and voltage-dependent Ca2+ channels, the PP-cells share fundamental regulatory mechanisms with other types of islet cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE CELLS PRODUCING pancreatic polypeptide (PP) are predominantly located in the islets of Langerhans found in the duodenal lobe of the pancreas (1). More than 95% of PP is of pancreatic origin (2). Although PP has several effects, it is difficult to identify an outstanding or dominating function (2, 3). Because PP reduces secretion from the exocrine pancreas, decreases gall bladder contraction, and inhibits gastric and small intestine motility, the hormone may pace the entry of nutrients into the circulation by slowing down the digestive process (2, 3).

Little is known about the signal transduction of PP secretion. We now present the first measurements of the cytoplasmic Ca2+ concentration ([Ca2+]i) in immuno-identified PP-cells exposed to different modulators of secretion. It is demonstrated that PP-cells express both voltage-dependent Ca2+ channels and ATP-regulated K+ (KATP) channels and that a direct stimulatory effect of glucose can be masked by somatostatin.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Reagents and solutions
Reagents of analytical grade and deionized water were used. Fura-2 and its acetoxymethyl ester were from Molecular Probes, Inc. (Eugene, OR). Atropine, carbachol, epinephrine, glycine, poly-L-lysine, HEPES, biotinylated rabbit anti-guinea-pig Ig, and BSA (fraction V) were provided by Sigma (St. Louis, MO). DAKO Corp. (Carpinteria, CA) supplied rabbit antihuman PP serum, guinea-pig antiporcine insulin serum, rabbit antihuman glucagon serum, rabbit antihuman somatostatin serum, biotinylated goat antirabbit Ig, normal goat serum, and 5-bromo-4-chloro-3-indoxyl phosphate plus nitro blue tetrazolium chloride. FCS was bought from Life Technologies Ltd. (Paisley, Scotland, UK), and collagenase was from Roche Molecular Biochemicals GmbH (Mannheim, Germany). Biolog Life Science Institute (Bremen, Germany) supplied 8-(4-chlorophenylthio)-adenosine-3',5'-cyclic monophosphorothioate, RP-isomer (RP-8-CPT-cAMPS). Diazoxide and methoxyverapamil were kindly donated by Schering-Plough Corp. Int. (Kenilworth, NJ) and Knoll Pharmaceutical Co. AG (Ludwigshafen, Germany), respectively, and forskolin plus tolbutamide by Hoechst Marion Roussel, Inc. AB, (Stockholm, Sweden).

Preparation of pancreatic islet cells
Islets of Langerhans were collagenase-isolated from pieces of pancreas from Naval Medical Research Institute mice. To obtain islets rich in PP-cells, only the lower duodenal part of the pancreas was used, as described for the rat (4). Free cells were prepared by shaking the islets in a Ca2+-deficient medium (5). The cells were suspended in RPMI 1640 medium supplemented with 10% FCS, 100 IU/ml penicillin, 100 µg/ml streptomycin, and 30 µg/ml gentamicin and were allowed to attach to poly-L-lysine-coated circular 25-mm coverslips, during 1–3 days culture, at 37 C, in RPMI 1640 medium, in an atmosphere of 5% CO2.

Image analysis of cytoplasmic Ca2+
Loading of cells with the indicator fura-2 was performed during 40-min incubation at 37 C in a HEPES-buffered medium (25 mM; pH 7.4) containing 0.5 mg/ml BSA, 138 mM NaCl, 5.9 mM KCl, 1.2 mM MgCl2, 1.28 mM CaCl2, 3 mM glucose, and 1 µM fura-2 acetoxymethyl ester (0.1% dimethylsulphoxide). The coverslips with the attached cells were then used as exchangeable bottoms of an open chamber thermostated at 37 C. The chamber vol was 0.16 ml, and the cells were superfused at a rate of 1 ml/min with a medium lacking indicator.

The Nikon Diaphot microscope (Nikon Europe B.V., Badhoevedorp, The Netherlands) was equipped with an epifluorescence illuminator and a 40x oil immersion fluorescence objective. A monochromator, which is part of a Quanticell 700 imaging system (VisiTech International, Sunderland, UK), provided excitation light flashes at 340 and 380 nm, and the emission was measured at 515 nm using an intensified CCD camera. Image pairs were taken every 1–2 sec, and 340/380 nm ratio (R) images were calculated after subtraction of background images. [Ca2+]i images were calculated according to Grynkiewicz et al. (6) using a dissociation constant (Kd) of 224 nM and the equation:

F0 and Rmin are the fura-2 fluorescence at 380 nm and the 340/380 nm fluorescence excitation ratio, respectively, in an intracellular K+-rich medium lacking Ca2+. FS and Rmax are the corresponding data obtained with a saturating concentration of Ca2+.

Identification of PP-cells
Each experiment was terminated with immunostaining of the cells in the experimental chamber. The cells were superfused with albumin-free medium and fixed with 95% ethanol. After rinsing with distilled water and Tris buffer (0.5 M, pH 7.6), normal goat serum (diluted 1:10) was added to reduce background staining. After 10 min, rabbit antihuman PP (1:200) was added for 20–30 min, followed by rinsing with Tris buffer. Biotinylated goat antirabbit Ig (1:500) was then introduced for 10 min, followed by rinsing and addition of alkaline phosphatase-conjugated streptavidine (1:200) for a further 10 min. The 5-bromo-4-chloro-3-indoxyl phosphate plus nitro blue tetrazolium chloride color reagent was then added for 2–5 min. In some experiments, a second staining for another hormone was performed using the same technique. Figure 1Go illustrates sequential staining for PP and insulin. In the latter case, guinea-pig antiporcine insulin (1:200) and biotinylated goat anti-guinea-pig Ig (1:500) were used. When identifying PP-cells together with {alpha}- or {delta}-cells, the second staining was performed with rabbit antihuman glucagon (1:200) or rabbit antihuman somatostatin (1:200) and biotinylated goat antirabbit Ig (1:500).



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  		Figure 1. Sequential staining for PP and insulin of three cells in which [Ca2+]i was measured (traces shown in Fig. 5Go). The upper panel shows that cells 1 and 2 are positive after the first staining for PP, and the lower panel shows that cell 3 also becomes positive after the second staining for insulin.

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The PP-cells were of similar size as the glucagon-secreting {alpha}-cells and somatostatin-secreting {delta}-cells but typically smaller than the insulin-secreting ß-cells (Fig. 1Go). With increasing experience of how the PP-cells react to different agents, it became clear that it is easier to functionally discriminate these cells from ß- and {delta}-cells than from {alpha}-cells. Indeed, there was no [Ca2+]i response characteristic for PP-cells alone.

[Ca2+]i remained stable below 100 nM in all PP-cells superfused with medium containing 3 mM glucose. Introduction of 5 µM epinephrine for 3–6 min induced a prompt, pronounced, and rapidly reversible elevation of [Ca2+]i in about 80% of the PP-cells (42 out of 53; Figs. 2Go, 3Go, 4Go, 5Go, 6Go, and 7Go). When epinephrine was present for longer periods of time, there were slow oscillations of [Ca2+]i (0.1–0.2/min) in 6 (Figs. 3Go, 5Go, and 7Go) and sustained elevation (Fig. 5Go) in two out of eight responsive PP-cells. The effects of epinephrine were rapidly inhibited by 400 µM of the hyperpolarizing KATP channel activator diazoxide (Fig. 3Go), 50 µM of the voltage-dependent Ca2+ channel blocker methoxyverapamil (not shown) and 100 nM somatostatin (not shown) in all out of four, two and two cells, respectively. The protein kinase A inhibitor RP-8-CPT-cAMPS (20 µM) blocked epinephrine-induced oscillations in two (Fig. 7Go) and transformed sustained elevation of [Ca2+]i into oscillations in two out of four cells (not shown). Elevation of cAMP by introduction of 5 µM forskolin mimicked the Ca2+-elevating effect of epinephrine in two out of three PP-cells (Fig. 5Go).



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  		Figure 2. Effects of epinephrine, tolbutamide, carbachol, and methoxyverapamil on [Ca2+]i of two simultaneously studied PP-cells. The fura-2-loaded PP-cells were initially exposed to a medium containing 3 mM glucose. Epinephrine (E; 5 µM), tolbutamide (T; 1 mM), carbachol (20 µM), and methoxyverapamil (50 µM) were then added as indicated.

 


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  		Figure 3. Effects of epinephrine, diazoxide, and carbachol on [Ca2+]i of two simultaneously studied PP-cells. The fura-2-loaded PP-cells were initially exposed to a medium containing 3 mM glucose. E (5 µM), diazoxide (D; 400 µM), and carbachol (20 µM) were then present, as indicated.

 


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  		Figure 4. Effects of E, tolbutamide, carbachol, glycine, and glucose on [Ca2+]i of two simultaneously studied PP-cells. The fura-2-loaded PP-cells were initially exposed to a medium containing 3 mM glucose. E (5 µM), T (1 mM), carbachol (Carb; 20 µM), glycine (3 mM), and glucose (16 mM) were then present, as indicated.

 


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  		Figure 5. Effects of E, T, forskolin, carbachol, and atropine on [Ca2+]i of two simultaneously studied PP-cells and one ß-cell. The fura-2-loaded cells were initially exposed to medium containing 3 mM glucose. E (5 µM), T (0.5 mM), forskolin (5 µM), carbachol (20 µM), and atropine (Atrop; 10 µM) were then present, as indicated. The numbers refer to the immunostained cells in Fig. 1Go.

 


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  		Figure 6. Effects of E, T, glycine, and glucose on [Ca2+]i of three separately studied PP-cells. The fura-2-loaded PP-cells were initially exposed to media containing 3 mM glucose. E (5 µM), T (0.5 mM in the upper panel and 1 mM in the middle and lower panels), glycine (3 mM), and glucose (0, 16, or 20 mM) were then present, as indicated.

 


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  		Figure 7. Effects of T, glucose, E, carbachol, RP-8-CPT-cAMPS, and somatostatin on [Ca2+]i of three separately studied PP-cells. The fura-2-loaded PP-cells were initially exposed to media containing 3 mM glucose. E (5 µM), T (0.5 mM), carbachol (20 µM), RP-8-CPT-cAMPS (RP; 20 µM), glucose (20 mM), and somatostatin (Som; 100 nM) were then present, as indicated.

 
Although the proportion of PP-cells with a [Ca2+]i response to 20 µM carbachol (25 out of 32 cells; Figs. 2–5GoGoGoGo, and 7) was similar to that seen after adding epinephrine, all cells did not react to both agents (Fig. 3Go). In most PP-cells, the response was either a single [Ca2+]i peak (Figs. 2Go and 4Go) or a peak followed by sustained elevation (Fig. 5Go). However, in 9 cells, carbachol induced sustained oscillations of [Ca2+]i (0.1–0.3/min; Figs. 2Go, 3Go, and 7Go). The effects of carbachol were rapidly inhibited by 400 µM diazoxide (Fig. 3Go), 50 µM methoxyverapamil (Fig. 2Go), 100 nM somatostatin (not shown), and 10 µM atropine (Fig. 5Go), but not by 20 µM RP-8-CPT-cAMPS (Fig. 7Go), in all out of 2, 3, 2, 3, and 3 cells, respectively.

The hypoglycemic sulfonylurea tolbutamide (0.5–1 mM) induced a prompt and rapidly reversible elevation of [Ca2+]i in 26 out of 48 PP-cells exposed to 3 mM glucose (Figs. 2Go and 4Go–7). When tolbutamide was present for longer periods of time, there were slow oscillations of [Ca2+]i in 3 cells (not shown). Elevation of glucose from 3 to 11 mM had no effect in 2 PP-cells, but 20 mM triggered a single [Ca2+]i peak or slow oscillations in 4 out of 7 cells (Fig. 7Go). Both the effects of tolbutamide and glucose were rapidly inhibited by 100 nM somatostatin in 3 and 1 cells, respectively (Fig. 7Go). When 3 mM glycine was introduced, in the presence of 3 mM glucose, 3 out of 9 PP-cells reacted with elevation of [Ca2+]i, ranging from a single peak to oscillations (Figs. 4Go and 6Go). Also, the {alpha}-cells were very sensitive to 3 mM glycine, whereas the ß- and {delta}-cells did not react (not shown). After elevation of glucose to 16 or 20 mM, in the continued presence of 3 mM glycine, 6 out of 9 PP-cells responded. In one experiment, a PP-cell reacted to 10 mM glycine with sustained elevation of [Ca2+]i, and this effect was promptly inhibited by 50 µM methoxyverapamil (not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Previous studies of PP-cell physiology have been based on measurements of the circulating hormone or hormone present in pancreas perfusates. This means that the responses observed reflect populations of PP-cells under paracrine influence from other islet cell types. We have now investigated how different agents affect [Ca2+]i, a key regulator of the secretory activity in various types of cells. Studying individual cells, it was possible to discriminate between direct and indirect effects of agents reported to modulate circulating PP. In accordance with our observations in other types of islet cells (7, 8, 9), there was often a considerable variability in the [Ca2+]i responses among individual PP-cells. This variability complicates the interpretation of the data and indicates that a smoothly graded response is a summation effect in a cell population. Other problems, when characterizing the [Ca2+]i signaling of the PP-cells, were their scarcity and the fact that they could be unequivocally identified only at the end of the experiments. The methodological difficulties associated with PP-cells probably explain why these cells have not previously been the subject of direct analyses.

Release of PP from the pancreas is primarily under vagal control, and the plasma concentration increases rapidly after consumption of a meal (10). It is therefore not surprising that a great majority of the tested PP-cells reacted with elevation of [Ca2+]i in response to the cholinergic agonist carbachol. Being blocked by atropine, this effect is apparently mediated by a muscarinic mechanism. As in the pancreatic ß-cell (11), the muscarinic activation can be expected to involve inositol 1,4,5-tris-phosphate-mediated mobilization of intracellular Ca2+. However, as shown in the present experiments, depolarization, with opening of voltage-dependent Ca2+ channels, is also involved. The action of carbachol was thus inhibited both by the Ca2+ channel blocker methoxyverapamil and by diazoxide, which hyperpolarizes the ß-cells by activating the KATP channels (12). It remains to be decided whether depolarization involves similar mechanisms, as proposed for the ß-cells, with activation of a store-operated current (11, 13, 14) and/or a direct activation of a Na+ current (15). The effect of carbachol apparently is mediated by a mechanism other than the increase of cAMP, because it was not prevented by the protein kinase A inhibitor RP-8-CPT-cAMPS.

Apart from responding to food intake, the secretion of PP is promoted by insulin-induced hypoglycemia (2, 3). Because the latter effect may involve elevation of circulating epinephrine, it is notable that the release of human PP is stimulated by ß-adrenergic activation (16). However, activation of {alpha}-adrenergic receptors has been found to inhibit secretion (16), perhaps explaining why there is only a little adrenergic contribution to hypoglycemia-induced PP secretion in the rat (17) and no contribution in the mouse (18). It was now observed that mouse PP-cells usually react to epinephrine, with prompt elevation of [Ca2+]i. Being effectively blocked by RP-8-CPT-cAMPS and mimicked by the adenylate cyclase activator forskolin, this action is apparently caused by activation of ß-adrenergic receptors. We have previously reported that also glucagon-producing {alpha}-cells respond to epinephrine, with increase of [Ca2+]i mediated by cAMP (9, 19). The initial effect of epinephrine on the {alpha}-cells persists when preventing the entry of Ca2+. It was now observed that the epinephrine-induced elevation of [Ca2+]i in PP-cells is promptly reversed by methoxyverapamil and diazoxide. These observations do not necessarily mean that different mechanisms are operating. We have not tested whether the initial response to epinephrine in PP-cells involves intracellular mobilization of Ca2+. Moreover, it remains to be established whether depolarization, with opening of voltage-dependent Ca2+ channels, contributes to the epinephrine response in the {alpha}-cells.

Protein-rich meals elicit a strong stimulatory effect on PP release, and amino acids have been found to potentiate such secretion (20). We now observed that some PP-cells responded to 3 mM glycine, with slow oscillations of [Ca2+]i. In responding to 3 mM glycine, the PP-cells mimicked the {alpha}-cells but differed from the ß- and {delta}-cells. It is likely that the effect of glycine on the PP-cells is attributable to depolarization with opening of voltage-dependent Ca2+ channels, given that it disappeared in the presence of methoxyverapamil. At higher concentrations of glycine, the rate of Na+ entry obtained by cotransport with the amino acid is sufficient to depolarize also the ß-cell (21).

The effect of glucose on PP secretion is complex. iv infusion of glucose is known to inhibit the release of PP (22, 23), but this action may be indirectly mediated either by glucose suppression of cholinergic activity (24) or stimulation of somatostatin secretion (25). Indeed, somatostatin antibodies have been found to reverse the inhibitory effect of glucose on PP release into stimulation (26). The present observations provide ample support for the idea that somatostatin masks a direct stimulatory effect of glucose on the PP-cells. In the pancreatic ß- and {delta}-cells, elevation of [Ca2+]i, in response to glucose, has been attributed to depolarization, with opening of voltage-dependent Ca2+ channels after closure of KATP channels (8, 27). The fact that a similar proportion of the PP-cells reacted to tolbutamide and glucose, with prompt elevation of [Ca2+]i, and that diazoxide induced a rapid lowering of [Ca2+]i in all PP cells, indicates the presence of KATP channels. The lack of effects of tolbutamide and glucose in some PP-cells may reflect the fact that the KATP channels are closed in these cells also under basal conditions. It is possible that activation of the KATP channels by a currently unidentified factor is important for shutting off PP secretion.

The present study is the first analysis of signal transduction in PP-secreting pancreatic islet cells. Because of the technical difficulty of these experiments, the number of cells studied was limited; and thus, some of the conclusions drawn should be considered preliminary. The results suggest that the PP-cells, like other types of islet cells, have KATP channels and voltage-dependent Ca2+ channels and that conditions known to stimulate PP secretion are associated with a depolarization-dependent elevation of [Ca2+]i.


   Footnotes
 
1 This study was supported by Grants 12X-562 and 12x-6240 from the Swedish Medical Research Council and by grants from the Swedish Foundation for Strategic Research, the Swedish Diabetes Association, the Novo Nordisk Foundation, Novo Nordisk Pharma AB, the Family Ernfors Foundation, the Åke Wiberg Foundation, and the Knut and Alice Wallenberg Foundation. Back

2 Present address: Department of Molecular Medicine, Veterinary Medical Center, Cornell University, Ithaca, New York 14853-6401. Back

Received May 21, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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