ORIGINAL ARTICLE
Pancreatic Endocrine Effects of Dopamine Receptors in Human Islet Cells Ying Zhang, MM,* Ruipan Zheng, MD,† Xiangzhi Meng, MM,* Lulu Wang, MD,* Li Liu, MD,* and Yan Gao, MD, PhD*
Objective: To date, there are no reports on the cellular localization of dopamine receptors in the human pancreas. In our study, we determined the localization and expression of 5 dopamine receptors (D1, D2, D3, D4, and D5) in normal human pancreas tissue. Methods: Human nonpathological pancreas tissues were fixed with 4% paraformaldehyde, paraffin-embedded, and processed for immunohistochemical analysis to detect dopamine receptors in the human pancreas tissue by using double immunofluorescent labeling and confocal microscopy. Results: We found that the D1 receptor is present in β cells; the D2 receptor is expressed by α, δ, and pancreatic polypeptide cells; the D4 receptor is expressed by β and polypeptide cells; whereas the D5 receptor is expressed only by δ cells. Conclusions: Our results identify the dopamine receptors (D1–D5) in normal pancreas tissue and provide a morphological basis for studying the pancreatic endocrine effects of dopamine and suggest a new target for the clinical treatment of diabetes. Key Words: dopamine, dopamine receptors, islets of Langerhans, insulin
cells produce insulin to lower glucose levels in the blood. The delta cells secrete somatostatin, which is a strong inhibitor of insulin and glucagon. Pancreatic polypeptide is secreted by PP cells in response to food ingestion, fasting, and exercise.6,7 Dopamine and its agonists are regulators of β-cell activity, but it is unclear whether dopamine is a promoter or inhibitor of insulin secretion.8,9 Since dopamine cannot cross the bloodbrain barrier, there are sources within the pancreas that allow dopamine to affect insulin secretion: (1) the nerve terminal surrounding pancreatic islets10; (2) exocrine pancreatic islet cells11; and (3) endocrine pancreatic cells.12 The messenger RNA from the 5 dopamine receptors has been isolated from mouse, rat, and human islet cells.12,13 Additionally, Rubi et al reported that the mouse INS-1E insulinoma cell line can synthesize and express D2DR.9 However, there are no reports on the localization and expression of dopamine receptors in the human pancreas. Therefore, the aim of our study was to identify the (D1–D5) dopamine receptors in normal pancreas tissue.
(Pancreas 2015;44: 925–929)
MATERIALS AND METHODS
D
opamine receptors belong to a class of G-protein-coupled receptors that are widely expressed in the central nervous system.1–4 There are 5 subtypes of dopamine receptors: D1 (D1DR), D2 (D2DR), D3 (D3DR), D4 (D4DR), and D5 (D5DR). D1 and D5 receptors are members of the D1-like family of receptors, whereas D2, D3, and D4 receptors are members of the D2-like family. In the presence of dopamine, D1-like receptors activate adenylyl cyclase, thereby increasing cyclic adenosine monophosphate. In contrast, activated D2-like receptors inhibit the production of cyclic adenosine monophosphate by inhibiting adenylyl cyclase.5 The endocrine function of the pancreas occurs in the islet of Langerhans, which primarily consists of alpha (α), beta (β), delta (δ), and pancreatic polypeptide (PP) cells types. The alpha cells secrete glucagon to increase blood glucose levels. The beta
From the *Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing; and †School of Medicine, Nankai University, Tianjin, China. Received for publication August 28, 2014; accepted January 13, 2015. Ying Zhang and Ruipan Zheng contributed equally to this work. Reprints: Yan Gao, MD, PhD, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, No.10 Xi Toutiao, You AnMen, Beijing, 100069, China (e‐mail: [email protected]). This work was supported by the National Natural Science Foundation of China (Grant No. 31171126, to Y. Gao). The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 6, August 2015
Human pancreases were obtained from patients with endocrine tumor with nonpathological endocrine islets in the Department of Pathology at Nanyang Central Hospital. All patients provided informed written consent. This study was approved by the Beijing Administration Office. Human pancreas tissue (7 μm) were fixed with 4% paraformaldehyde, paraffin-embedded, and processed for immunohistochemical analysis. For detecting dopamine receptors in the human pancreas tissue, antibodies against antirabbit D1DR (1:200, ab40653, Abcam, Cambridge Mass), D2DR (1:200, ADR-002, Alomone Labs, Jerusalem, Israel), D4DR (1:200, ab20424, Abcam), D5DR (1:200, ADR-005, Alomone Labs) were used. For hormone detection antibodies against antigoat glucagon (1:200, sc-7780, Santa Cruz Biotechnology, Santa Cruz, Calif ), antimouse insulin (1:800, 3014S, Cell Signaling Technology, Mass,), antimouse somatostatin (1:400, sc-25262, Santa Cruz Biotechnology), or antigoat PP (1:400, Lifespan Biosciences LS-c55231, www.Antibodypedia.com) were used. To visualize dopamine receptors, hormones, and cell nuclei (DAPI; 1:500, Sigma-Aldrich, St. Louis, Mo) sections were imaged using confocal microscopy (Leica, Solms, Germany).
RESULTS To visualize dopamine receptors in specific islet cell types, we performed immunofluorescence double staining experiments using antibodies specific for insulin (β cells), glucagon (α cells); somatostatin (SST; δ cells), and pancreatic polypetide (PPY; PP cells). As shown in Figure 1, D1DR localized to endocrine β cells compared to pancreatic acinar cells. The D2 dopamine receptor is www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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expressed by α, δ, and PP cells (Fig. 2). The D4 dopamine receptor is expressed by β and PP cells (Fig. 3), and the D5 receptor is expressed by δ cells (Fig. 4). We did not detect the D3 dopamine receptor in any islet cell type (data not shown).
DISCUSSION In our study, we found that human pancreatic islet cells express D1, D2, D4, and D5 dopamine receptors. Specifically, we
detected partial expression of D1DR in β cells, D2DR and D5DR in δ cells, and D2DR and D4DR in PP cells. These results suggest that insulin secretion can also occur by dopamine activation of receptors on α, δ, and PP cells. Previous in vitro studies have reported that dopamine can regulate insulin secretion.8,9 Shankar et al14 and Schuit et al15 demonstrated that insulin production is dependent on the concentration of dopamine. A low concentration of dopamine (10−8 M) stimulates insulin secretion in rats, whereas a high
FIGURE 1. D1 dopamine receptor is expressed by β islet cells. Immunofluorescence images of pancreas tissue sections illustrate colocalization of D1DR with glucagon, GLU (A); insulin, INS (E); somatostatin, SST (I); and pancreatic polypeptide PPY (M) expressing cells (square with dotted line). Sections (7 μm) were immunostained with anti-GLU (green), INS (red), SST (red), PPY (green) antibodies, and an anti-D1DR antibody (red in panels B and N; green in panels F and G), Cell nuclei (blue) are labeled with DAPI and white arrowheads depict colocalization. Editor’s note: A color image accompanies the online version of this article.
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© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 6, August 2015
Localization of Dopamine Receptors in the Pancreas
FIGURE 2. D2 dopamine receptor is expressed by α, δ, and PP islet cells. Immunofluorescence images of pancreas tissue sections illustrate colocalization of D2DR with GLU (A), INS (E), SST (I), and PPY (M) expressing cells. Sections (7 μm) were immunostained with anti-GLU (green), INS (red), SST (red), PPY (green) antibodies and an anti-D2DR antibody (red in panels B and N; green in panels F and G). Cell nuclei (blue) are labeled with DAPI, and white arrowheads depict colocalization. Editor’s note: A color image accompanies the online version of this article.
FIGURE 3. D4 dopamine receptor is present in β and PP islet cells. Immunofluorescence images of pancreas tissue sections represent colocalization of D4DR with GLU (A), INS (E), SST (I), PPY (M) expressing cells. Sections (7 μm) were immunostained with anti-GLU (green), INS (red), SST (red), PPY (green) antibodies, and an anti-D4DR antibody (red in panels B and N; green in panels F and G). Cell nuclei (blue) are labeled with DAPI, and white arrowheads depict colocalization. Editor’s note: A color image accompanies the online version of this article. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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FIGURE 4. D5 dopamine receptor is expressed by δ islet cells. Immunofluorescent images of pancreas tissue sections represent colocalization of D5DR with GLU (A), INS (E), SST (I), and PPY (M) expressing cells. Sections (7 μm) were immunostained with anti-GLU (green), INS (red), SST (red), PPY (green) antibodies, and an anti-D5DR antibody (red in panels B and N; green in panels F and G); DAPI was used to label nuclei (blue). Cell nuclei (blue) are labeled with DAPI, and white arrowheads depict colocalization. Editor’s note: A color image accompanies the online version of this article.
concentration of dopamine (10−7 to 10−4 M) inhibits insulin production in both rats and mice.14,15 Garcia-Tornadu et al16 found that activation of D2DR on rat islet β cells can stimulate insulin secretion. Furthermore, Rubi et al9 isolated D1DR, D2DR, D3DR, D4DR, and D5DR messenger RNA from β cells in mice, rat, and human islet cells. However, we show expression of D1DR and D4DR in human islet β cells in vivo. These variations may result from differences in study objective, study design, and species used. We and others report that pancreatic endocrine cells can synthesize different proteins depending on their environment.6
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In conclusion, our study provides a morphological basis for further studies on dopamine-mediated insulin production while providing a new target for the treatment of type 2 diabetes. REFERENCES 1. Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63:182–217. 2. Khan ZU, Mrzljak L, Gutierrez A, et al. Prominence of the dopamine D2 short isoform in dopaminergic pathways. Proc Natl Acad Sci U S A. 1998; 95:7731–7736.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 6, August 2015
3. Wood-Kaczmar A, Gandhi S, Wood NW. Understanding the molecular causes of Parkinson's disease. Trends Mol Med. 2006;12: 521–528. 4. Rubi B, Maechler P. Minireview: new roles for peripheral dopamine on metabolic control and tumor growth: let's seek the balance. Endocrinology. 2010;151:5570–5581.
Localization of Dopamine Receptors in the Pancreas
10. Taborsky GJ Jr. The physiology of glucagon. J Diabetes Sci Technol. 2010;4:1338–1344. 11. Mezey E, Eisenhofer G, Harta G, et al. A novel nonneuronalcatecholaminergic system: exocrine pancreas synthesizes and releases dopamine. Proc Natl Acad Sci U S A. 1996;93:10377–10382.
5. Vallone D, Picetti R, Borrelli E. Structure and function of dopamine receptors. Neurosci Biobehav Rev. 2000;24:125–132.
12. Ustione A, Piston DW. Dopamine synthesis and D3 receptor activation in pancreatic beta-cells regulates insulin secretion and intracellular [Ca(2+)] oscillations. Mol Endocrinol. 2012;26:1928–1940.
6. Ruipan Z, Xiangzhi M, Li L, et al. Differential expression and localization of neuropeptide Y peptide in pancreatic islet of diabetic and high fat fed rats. Peptides. 2014;54:33–38.
13. Chen Y, Hong F, Chen H, et al. Distinctive expression and cellular distribution of dopamine receptors in the pancreatic islets of rats. Cell Tissue Res. 2014.
7. Matschinsky FM, Ellerman JE. Metabolism of glucose in the islets of Langerhans. J Biol Chem. 1968;243:2730–2736.
14. Shankar E, Santhosh KT, Paulose CS. Dopaminergic regulation of glucose-induced insulin secretion through dopamine D2 receptors in the pancreatic islets in vitro. IUBMB Life. 2006;58:157–163.
8. Melkersson K, Khan A, Hilding A, et al. Different effects of antipsychotic drugs on insulin release in vitro. Eur Neuropsychopharmacol. 2001;11: 327–332. 9. Rubi B, Ljubicic S, Pournourmohammadi S, et al. Dopamine D2-like receptors are expressed in pancreatic beta cells and mediate inhibition of insulin secretion. J Biol Chem. 2005;280: 36824–36832.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
15. Schuit FC, Huypens P, Heimberg H, et al. Glucose sensing in pancreatic beta-cells: a model for the study of other glucose-regulated cells in gut, pancreas, and hypothalamus. Diabetes. 2001;50:1–11. 16. Garcia-Tornadu I, Ornstein AM, Chamson-Reig A, et al. Disruption of the dopamine d2 receptor impairs insulin secretion and causes glucose intolerance. Endocrinology. 2010;151:1441–1450.
www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Pancreatic Endocrine Effects of Dopamine Receptors in Human Islet Cells Ying Zhang, MM,* Ruipan Zheng, MD,† Xiangzhi Meng, MM,* Lulu Wang, MD,* Li Liu, MD,* and Yan Gao, MD, PhD*
Objective: To date, there are no reports on the cellular localization of dopamine receptors in the human pancreas. In our study, we determined the localization and expression of 5 dopamine receptors (D1, D2, D3, D4, and D5) in normal human pancreas tissue. Methods: Human nonpathological pancreas tissues were fixed with 4% paraformaldehyde, paraffin-embedded, and processed for immunohistochemical analysis to detect dopamine receptors in the human pancreas tissue by using double immunofluorescent labeling and confocal microscopy. Results: We found that the D1 receptor is present in β cells; the D2 receptor is expressed by α, δ, and pancreatic polypeptide cells; the D4 receptor is expressed by β and polypeptide cells; whereas the D5 receptor is expressed only by δ cells. Conclusions: Our results identify the dopamine receptors (D1–D5) in normal pancreas tissue and provide a morphological basis for studying the pancreatic endocrine effects of dopamine and suggest a new target for the clinical treatment of diabetes. Key Words: dopamine, dopamine receptors, islets of Langerhans, insulin
cells produce insulin to lower glucose levels in the blood. The delta cells secrete somatostatin, which is a strong inhibitor of insulin and glucagon. Pancreatic polypeptide is secreted by PP cells in response to food ingestion, fasting, and exercise.6,7 Dopamine and its agonists are regulators of β-cell activity, but it is unclear whether dopamine is a promoter or inhibitor of insulin secretion.8,9 Since dopamine cannot cross the bloodbrain barrier, there are sources within the pancreas that allow dopamine to affect insulin secretion: (1) the nerve terminal surrounding pancreatic islets10; (2) exocrine pancreatic islet cells11; and (3) endocrine pancreatic cells.12 The messenger RNA from the 5 dopamine receptors has been isolated from mouse, rat, and human islet cells.12,13 Additionally, Rubi et al reported that the mouse INS-1E insulinoma cell line can synthesize and express D2DR.9 However, there are no reports on the localization and expression of dopamine receptors in the human pancreas. Therefore, the aim of our study was to identify the (D1–D5) dopamine receptors in normal pancreas tissue.
(Pancreas 2015;44: 925–929)
MATERIALS AND METHODS
D
opamine receptors belong to a class of G-protein-coupled receptors that are widely expressed in the central nervous system.1–4 There are 5 subtypes of dopamine receptors: D1 (D1DR), D2 (D2DR), D3 (D3DR), D4 (D4DR), and D5 (D5DR). D1 and D5 receptors are members of the D1-like family of receptors, whereas D2, D3, and D4 receptors are members of the D2-like family. In the presence of dopamine, D1-like receptors activate adenylyl cyclase, thereby increasing cyclic adenosine monophosphate. In contrast, activated D2-like receptors inhibit the production of cyclic adenosine monophosphate by inhibiting adenylyl cyclase.5 The endocrine function of the pancreas occurs in the islet of Langerhans, which primarily consists of alpha (α), beta (β), delta (δ), and pancreatic polypeptide (PP) cells types. The alpha cells secrete glucagon to increase blood glucose levels. The beta
From the *Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing; and †School of Medicine, Nankai University, Tianjin, China. Received for publication August 28, 2014; accepted January 13, 2015. Ying Zhang and Ruipan Zheng contributed equally to this work. Reprints: Yan Gao, MD, PhD, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, No.10 Xi Toutiao, You AnMen, Beijing, 100069, China (e‐mail: [email protected]). This work was supported by the National Natural Science Foundation of China (Grant No. 31171126, to Y. Gao). The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 6, August 2015
Human pancreases were obtained from patients with endocrine tumor with nonpathological endocrine islets in the Department of Pathology at Nanyang Central Hospital. All patients provided informed written consent. This study was approved by the Beijing Administration Office. Human pancreas tissue (7 μm) were fixed with 4% paraformaldehyde, paraffin-embedded, and processed for immunohistochemical analysis. For detecting dopamine receptors in the human pancreas tissue, antibodies against antirabbit D1DR (1:200, ab40653, Abcam, Cambridge Mass), D2DR (1:200, ADR-002, Alomone Labs, Jerusalem, Israel), D4DR (1:200, ab20424, Abcam), D5DR (1:200, ADR-005, Alomone Labs) were used. For hormone detection antibodies against antigoat glucagon (1:200, sc-7780, Santa Cruz Biotechnology, Santa Cruz, Calif ), antimouse insulin (1:800, 3014S, Cell Signaling Technology, Mass,), antimouse somatostatin (1:400, sc-25262, Santa Cruz Biotechnology), or antigoat PP (1:400, Lifespan Biosciences LS-c55231, www.Antibodypedia.com) were used. To visualize dopamine receptors, hormones, and cell nuclei (DAPI; 1:500, Sigma-Aldrich, St. Louis, Mo) sections were imaged using confocal microscopy (Leica, Solms, Germany).
RESULTS To visualize dopamine receptors in specific islet cell types, we performed immunofluorescence double staining experiments using antibodies specific for insulin (β cells), glucagon (α cells); somatostatin (SST; δ cells), and pancreatic polypetide (PPY; PP cells). As shown in Figure 1, D1DR localized to endocrine β cells compared to pancreatic acinar cells. The D2 dopamine receptor is www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Zhang et al
expressed by α, δ, and PP cells (Fig. 2). The D4 dopamine receptor is expressed by β and PP cells (Fig. 3), and the D5 receptor is expressed by δ cells (Fig. 4). We did not detect the D3 dopamine receptor in any islet cell type (data not shown).
DISCUSSION In our study, we found that human pancreatic islet cells express D1, D2, D4, and D5 dopamine receptors. Specifically, we
detected partial expression of D1DR in β cells, D2DR and D5DR in δ cells, and D2DR and D4DR in PP cells. These results suggest that insulin secretion can also occur by dopamine activation of receptors on α, δ, and PP cells. Previous in vitro studies have reported that dopamine can regulate insulin secretion.8,9 Shankar et al14 and Schuit et al15 demonstrated that insulin production is dependent on the concentration of dopamine. A low concentration of dopamine (10−8 M) stimulates insulin secretion in rats, whereas a high
FIGURE 1. D1 dopamine receptor is expressed by β islet cells. Immunofluorescence images of pancreas tissue sections illustrate colocalization of D1DR with glucagon, GLU (A); insulin, INS (E); somatostatin, SST (I); and pancreatic polypeptide PPY (M) expressing cells (square with dotted line). Sections (7 μm) were immunostained with anti-GLU (green), INS (red), SST (red), PPY (green) antibodies, and an anti-D1DR antibody (red in panels B and N; green in panels F and G), Cell nuclei (blue) are labeled with DAPI and white arrowheads depict colocalization. Editor’s note: A color image accompanies the online version of this article.
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© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 6, August 2015
Localization of Dopamine Receptors in the Pancreas
FIGURE 2. D2 dopamine receptor is expressed by α, δ, and PP islet cells. Immunofluorescence images of pancreas tissue sections illustrate colocalization of D2DR with GLU (A), INS (E), SST (I), and PPY (M) expressing cells. Sections (7 μm) were immunostained with anti-GLU (green), INS (red), SST (red), PPY (green) antibodies and an anti-D2DR antibody (red in panels B and N; green in panels F and G). Cell nuclei (blue) are labeled with DAPI, and white arrowheads depict colocalization. Editor’s note: A color image accompanies the online version of this article.
FIGURE 3. D4 dopamine receptor is present in β and PP islet cells. Immunofluorescence images of pancreas tissue sections represent colocalization of D4DR with GLU (A), INS (E), SST (I), PPY (M) expressing cells. Sections (7 μm) were immunostained with anti-GLU (green), INS (red), SST (red), PPY (green) antibodies, and an anti-D4DR antibody (red in panels B and N; green in panels F and G). Cell nuclei (blue) are labeled with DAPI, and white arrowheads depict colocalization. Editor’s note: A color image accompanies the online version of this article. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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FIGURE 4. D5 dopamine receptor is expressed by δ islet cells. Immunofluorescent images of pancreas tissue sections represent colocalization of D5DR with GLU (A), INS (E), SST (I), and PPY (M) expressing cells. Sections (7 μm) were immunostained with anti-GLU (green), INS (red), SST (red), PPY (green) antibodies, and an anti-D5DR antibody (red in panels B and N; green in panels F and G); DAPI was used to label nuclei (blue). Cell nuclei (blue) are labeled with DAPI, and white arrowheads depict colocalization. Editor’s note: A color image accompanies the online version of this article.
concentration of dopamine (10−7 to 10−4 M) inhibits insulin production in both rats and mice.14,15 Garcia-Tornadu et al16 found that activation of D2DR on rat islet β cells can stimulate insulin secretion. Furthermore, Rubi et al9 isolated D1DR, D2DR, D3DR, D4DR, and D5DR messenger RNA from β cells in mice, rat, and human islet cells. However, we show expression of D1DR and D4DR in human islet β cells in vivo. These variations may result from differences in study objective, study design, and species used. We and others report that pancreatic endocrine cells can synthesize different proteins depending on their environment.6
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In conclusion, our study provides a morphological basis for further studies on dopamine-mediated insulin production while providing a new target for the treatment of type 2 diabetes. REFERENCES 1. Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63:182–217. 2. Khan ZU, Mrzljak L, Gutierrez A, et al. Prominence of the dopamine D2 short isoform in dopaminergic pathways. Proc Natl Acad Sci U S A. 1998; 95:7731–7736.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 6, August 2015
3. Wood-Kaczmar A, Gandhi S, Wood NW. Understanding the molecular causes of Parkinson's disease. Trends Mol Med. 2006;12: 521–528. 4. Rubi B, Maechler P. Minireview: new roles for peripheral dopamine on metabolic control and tumor growth: let's seek the balance. Endocrinology. 2010;151:5570–5581.
Localization of Dopamine Receptors in the Pancreas
10. Taborsky GJ Jr. The physiology of glucagon. J Diabetes Sci Technol. 2010;4:1338–1344. 11. Mezey E, Eisenhofer G, Harta G, et al. A novel nonneuronalcatecholaminergic system: exocrine pancreas synthesizes and releases dopamine. Proc Natl Acad Sci U S A. 1996;93:10377–10382.
5. Vallone D, Picetti R, Borrelli E. Structure and function of dopamine receptors. Neurosci Biobehav Rev. 2000;24:125–132.
12. Ustione A, Piston DW. Dopamine synthesis and D3 receptor activation in pancreatic beta-cells regulates insulin secretion and intracellular [Ca(2+)] oscillations. Mol Endocrinol. 2012;26:1928–1940.
6. Ruipan Z, Xiangzhi M, Li L, et al. Differential expression and localization of neuropeptide Y peptide in pancreatic islet of diabetic and high fat fed rats. Peptides. 2014;54:33–38.
13. Chen Y, Hong F, Chen H, et al. Distinctive expression and cellular distribution of dopamine receptors in the pancreatic islets of rats. Cell Tissue Res. 2014.
7. Matschinsky FM, Ellerman JE. Metabolism of glucose in the islets of Langerhans. J Biol Chem. 1968;243:2730–2736.
14. Shankar E, Santhosh KT, Paulose CS. Dopaminergic regulation of glucose-induced insulin secretion through dopamine D2 receptors in the pancreatic islets in vitro. IUBMB Life. 2006;58:157–163.
8. Melkersson K, Khan A, Hilding A, et al. Different effects of antipsychotic drugs on insulin release in vitro. Eur Neuropsychopharmacol. 2001;11: 327–332. 9. Rubi B, Ljubicic S, Pournourmohammadi S, et al. Dopamine D2-like receptors are expressed in pancreatic beta cells and mediate inhibition of insulin secretion. J Biol Chem. 2005;280: 36824–36832.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
15. Schuit FC, Huypens P, Heimberg H, et al. Glucose sensing in pancreatic beta-cells: a model for the study of other glucose-regulated cells in gut, pancreas, and hypothalamus. Diabetes. 2001;50:1–11. 16. Garcia-Tornadu I, Ornstein AM, Chamson-Reig A, et al. Disruption of the dopamine d2 receptor impairs insulin secretion and causes glucose intolerance. Endocrinology. 2010;151:1441–1450.
www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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