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Somatostatin Acts Via a Pertussis Toxin-Sensitive Mechanism on Calcitonin Secretion in C-Cells

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Somatostatin Acts Via a Pertussis Toxin-Sensitive Mechanism on Calcitonin Secretion in C-Cells Henry Ford Hospital Medical Journal Volume 40 Number 3 Article 35 9-1992 Somatostatin Acts Via a Pertussis Toxin-Sensitive Mechanism on Calcitonin Secretion in C-Cells Angela Zink Hans Scherubl Friedhelm Raue Reinhard Ziegler Follow this and additional works at: https://scholarlycommons.henryford.com/hfhmedjournal Part of the Life Sciences Commons, Medical Specialties Commons, and the Public Health Commons Recommended Citation Zink, Angela; Scherubl, Hans; Raue, Friedhelm; and Ziegler, Reinhard (1992) "Somatostatin Acts Via a Pertussis Toxin-Sensitive Mechanism on Calcitonin Secretion in C-Cells," Henry Ford Hospital Medical Journal : Vol. 40 : No. 3 , 289-292. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol40/iss3/35 This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Somatostatin Acts Via a Pertussis Toxin-Sensitive Mechanism on Calcitonin Secretion in C-Cells Angela Zink,* Hans Scherubl,^ Friedhelm Raue,* and Reinhard Ziegler' The effect ofthe somatostatin analog octreotide on cAMP-mediated calcitonin (CT) secretion and cAMP accumulation in C-cells was investigated. Glucagon stimulated cAMP accumulation and CT secretion with a maximal eff'ecl at a concentration oflQ-^M. The cAMP antagonist RpcAMPs blocked the glucagon-induced CT secretion down to control levels. Therefore, no other second messengers seem to he involved in glucagon-stimulated CT secretion. Octreotide in increasing doses (70'' to 10'^ M) inhibited cAMP accumulation and CT secretion with a maximal effect at a concentration of 10'^ (40% and 29% of control values, respectively). Pretreatment ofthe cells with 100 ng/mL pertussis toxin for 24 hours abolished the inhibitory effect of octreotide on cAMP accumulation and CT secretion (82% and 58% of control values, respectively). Similar results were obtained under the inftuence ofthe phosphodiesterase inhibitor IBMX. Therefore, we conclude that somatostatin modu­ lates adenylate cyclase-coupled CT secretion in C-cells via a pertussis toxin-sensitive G-protein possibly in an autocrine/paracrine way. (Henry Ford Hosp MedJ 1992:40:289-92) omatostatin is a physiologically important inhibitor of Determination of cAMP S growth hormone release and is also known to inhibit Confluent cells on 35 mm dishes were washed twice with hormone secretion in a variety of extrapituitary tissues includ­ PBS-buffer and further incubated with medium containing test ing brain, thyroid, pancreas, and gut (1,2). Concerning C-cells in agents or vehicle alone at 37 °C. After 15 minutes, medium was vivo, somatostatin inhibits calcitonin (CT) secretion (3,4), but removed, cells were washed twice with PBS-buffer, and denatu- the physiological role of somatostatin and the mechanism of ac­ rated with ice-cold ethanol (100% pH 3). After 2 hours at 4 °C, tion in CT-secreting cells is still unclear. the supematant was evaporated at 37 °C under Nj and the result­ Hormone secretion by C-cells is mainly regulated through ing pellet was resuspended in the cAMP-assay buffer. cAMP changes in the extracellular calcium concentration via voltage- was determined by competitive protein binding assay as re­ dependent calcium channels, but various peptides such as glu­ ported previously (8). Total cell protein was determined by the cagon or growth hormone-releasing peptide influence CT secre­ method of Bradford (9). tion in C-cells via the adenylate cyclase pathway (5). It has been shown that in pituitary eeds somatostatin acts independently on Secretion experiments both second messenger systems, the cAMP-mediated and the To determine CT secretion, confluent cells on replicate 35 calcium-mediated pathway (6). In C-cells, the effect of somato­ mm dishes were preincubated with serum-free DMEM for 2 statin on adenylate cyclase-mediated CT secretion is still un­ hours. Subsequently, ceUs were washed twice with PBS-buffer clear. Therefore, we studied the effect of somatostatin on the and further incubated with medium containing test agents or ve­ glucagon-stimulated CT secretion in an established rat medul­ hicle alone. After 2 hours, medium from each dish was collected lary carcinoma cell line (rMTC 6-23) (7) in order to elucidate the and stored at -20 °C until assayed. CT was measured by radio­ role of somatostatin on cAMP-mediated CT secretion and to immunoassay. Total cell protein was determined after die study the possible involvement of a pertussis toxin-sensitive method of Bradford (9). Viability as tested by trypan blue exclu­ mechanism in cAMP-mediated CT secretion. sion was > 90% in each experiment. Methods Cell culture rMTC 6-23 cells were purchased from the American Type Submitted for publication: Oclober 14, I99I. Culture Collection and grown as monolayers in Dulbecco's Accepted for publication: November 27, 1991. *Department of Intemal Medicine 1, Endocrinology and Metabolism, University of Hei­ modified Eagle's medium (DMEM) supplemented with 15% delberg, Heidelberg. Germany, horse seram in a humidified atmosphere with 5% COj and 95% -j-Pharmakologischesln.stitul derFreien Universitat Berlin, Beriin, Germany. Address correspondence to Dr. Zink, Departnient of Intemal Medicine 1, Endocrinology, air. Luisenstrabe 5, D-6900 Heidelberg, Germany. Henry Ford Hosp Med 1—Vol 40, Nos 3 & 4, 1992 Effect of Somatostatin on CT Secretion in C-cells—Zink et al 289 Table Effect ofthe cAMP Antagonist RpcAMPs on 600 Glucagon-induced Calcitonin Secretion in rMTC Cells* ^ 500 Calcitonin Secretion 400 (pg CT/mg Protein/2 hrs) 300 - Control 60 + 4.8 £ Glucagon (10-'' M) 124 ±9 a 200 RpcAMPs (1 O't M) 59 ±7 < Glucagon (IQ-^ M) 4- RpcAMPs (10"* M) 61 ±9 100 *Points show mean ± SEM of four representative experiments. 300 and reached levels 300% and 150% over control levels for OJ cAMP and CT secretion, respectively. The cAMP antagonist ^ 200 RpcAMPs blocked the glucagon-induced CT secretion down to 9) control values (Table). Increasing doses of octreotide (10"^ to O 10"* M) inhibited the glucagon-induced cAMP accumulation o. and CT secretion maximally to 40% and 29%, respectively, by a concentration of 10"^ M octreotide (Fig 2). Similar results were 100 I- seen under the influence of the phosphodiesterase inhibitor 2 IBMX (10'"* M, data not shown). Fig 3 shows the effect of pre­ treatment of the cells for 24 hours with pertussis toxin. This pre­ treatment partially blocked the inhibitory effect of octreotide on cAMP accumulation and CT secretion to 82% and 58% of con­ Glucagon 6 -lg(M) trol values, respectively (Fig 3). A maximal effect of pertussis toxin was reached by a concentration of 100 ng/mL. Similar re­ sults were obtained under the influence of IBMX (10M, data Fig 1—Effect of increasing doses of glucagon on cAMP accu­ not shown). mulation (upper panel) and CT secretion (lower panel) in rMTC cells. Cells were grown and experiments performed as de­ scrihed in the text. Points represent mean ± SEM of four repre­ Discussion sentative experiments. The glucagon-induced CT secretion in our experiments paral­ leled the glucagon-induced cAMP accumulation, which is con­ sistent with previous findings (5). Generation of other second Materials messengers such as IP3, which influences intracellular calcium DMEM and trypsin/EDTA were obtained from Biochrom by glucagon, is unlikely in C-cells, as it has been shown eartier (Berlin, Germany) and L-glutamine, HEPES-buffer, PBS- that glucagon had no ef fect on intracellular calcium concentra­ buffer, and horse seram from Gibco (Paisley, UK). Glucagon tion in C-cells measured with fura-2-loaded cells (10). Further­ and pertussis toxin were purchased by Sigma (Deisenhofen, more, addition of the cAMP antagonist RpcAMPS completely Germany). The cyclic somatostatin analog octreotide was a gift suppressed glucagon-stimulated CT secretion. Therefore, we from Sandoz (Nuraberg, Germany). Plastic tissue culture ware considered activation of adenylate cyclase the sole signal- was purchased from Falcon (Los Angeles, CA). transducing pathway mediating the glucagon-induced CT secre­ tion in our cell system and used it as a model to study the effect of somatostatin on cAMP-mediated CT secretion. Statistics Somatostatin is able to inhibit cAMP accumulation as well as Data are represented as means ± SEM. Statistical analysis was cAMP-mediated CT-secretion in C-cells. This is consistent with performed using the computer program STATVIEW (Abacus findings in pituitary or adrenal glomerulosa cells, where so­ Concepts, Inc., Berkeley, CA). Statistical significance was as­ matostatin inhibits cAMP-mediated hormone secretion in a sim­ sessed by Wilcoxon rank sum test or the Mann-Whitney- ilar way (11,12). In the rMTC 6-23 cells as well as in parafolli­ Wilcoxon test; P < 0.05 was considered significant. cular and GH-pituitary cells, the inhibitory effect of somato­ statin was not complete (13-15). The reason for this is unclear. Results Binding studies with different somatostatin analogs revealed Glucagon stimulated cAMP accumulation and CT secretion similar or even higher binding affinities or biological effects of in rMTC 6-23 cells in a dose-dependent manner as shown in Fig the analogs in pituitary cells (16). Thus stmctural differences are 1. Maximal stimulation occurred at a concentration of 10"^ M not likely to be the reason for this partial inhibitory effect. As C- 290 Henry Ford Hosp Med J—Vol 40, Nos 3 & 4, 1992 Effeci of Somatostatin on CT Secretion in C-cell.s—Zink et al = 100 c •fii o a1— o> E < o a 200 c 1 •fij o o u. 100 o> £ E la: o Gl Cl Glucagon 0 7 -lg(M) Ilili Octreotide 0 9 -lg(M) Glucagon 07707707 7 -lg(M) Octreotide 00700700 7 -lg(M) Fig 2—Effect of increasing doses of octreotide on glucagon- PT 0 0 0 10 10 10 100 100 100 ng/ml stimulated cAMP accumulation (upper panel) and CT secretion (lower panel) in rMTC cells.
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