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Research ArticleEndocrine and Diabetes

The Role of Voltage-Gated Potassium Channels Kv2.1 and Kv2.2 in the Regulation of Insulin and Somatostatin Release from Pancreatic Islets

Xiaoyan (Nina) Li, James Herrington, Aleksandr Petrov, Lan Ge, George Eiermann, Yusheng Xiong, Mette V. Jensen, Hans E. Hohmeier, Christopher B. Newgard, Maria L. Garcia, Michael Wagner, Bei B. Zhang, Nancy A. Thornberry, Andrew D. Howard, Gregory J. Kaczorowski and Yun-Ping Zhou
Journal of Pharmacology and Experimental Therapeutics February 2013, 344 (2) 407-416; DOI: https://doi.org/10.1124/jpet.112.199083
Xiaoyan (Nina) Li
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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James Herrington
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Aleksandr Petrov
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Lan Ge
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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George Eiermann
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Yusheng Xiong
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Mette V. Jensen
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Hans E. Hohmeier
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Christopher B. Newgard
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Maria L. Garcia
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Michael Wagner
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Bei B. Zhang
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Nancy A. Thornberry
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Andrew D. Howard
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Gregory J. Kaczorowski
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Yun-Ping Zhou
Department of Metabolic Disorders–Diabetes (X.L., L.G., B.B.Z., N.A.T., A.D.H., Y.-P. Z.), Department of Ion Channels (J.H., M.L.G., M.W., G.J.K.), Department of Pharmacology (A.P., G.E.), and Department of Medicinal Chemistry (Y.X.), Merck Research Laboratories, Rahway, New Jersey; and the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology, and Cancer Biology and Medicine, Duke University Medical Center, Durham, North Carolina (M.J., H.E.H., C.B.N.)
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Abstract

The voltage-gated potassium channels Kv2.1 and Kv2.2 are highly expressed in pancreatic islets, yet their contribution to islet hormone secretion is not fully understood. Here we investigate the role of Kv2 channels in pancreatic islets using a combination of genetic and pharmacologic approaches. Pancreatic β-cells from Kv2.1−/− mice possess reduced Kv current and display greater glucose-stimulated insulin secretion (GSIS) relative to WT β-cells. Inhibition of Kv2.x channels with selective peptidyl [guangxitoxin-1E (GxTX-1E)] or small molecule (RY796) inhibitors enhances GSIS in isolated wild-type (WT) mouse and human islets, but not in islets from Kv2.1−/− mice. However, in WT mice neither inhibitor improved glucose tolerance in vivo. GxTX-1E and RY796 enhanced somatostatin release in isolated human and mouse islets and in situ perfused pancreata from WT and Kv2.1−/− mice. Kv2.2 silencing in mouse islets by adenovirus-small hairpin RNA (shRNA) specifically enhanced islet somatostatin, but not insulin, secretion. In mice lacking somatostatin receptor 5, GxTX-1E stimulated insulin secretion and improved glucose tolerance. Collectively, these data show that Kv2.1 regulates insulin secretion in β-cells and Kv2.2 modulates somatostatin release in δ-cells. Development of selective Kv2.1 inhibitors without cross inhibition of Kv2.2 may provide new avenues to promote GSIS for the treatment of type 2 diabetes.

Footnotes

  • dx.doi.org/10.1124/jpet.112.199083.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Received August 3, 2012.
  • Accepted November 15, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 2
1 Feb 2013
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Research ArticleEndocrine and Diabetes

Distinct Roles of Kv2.1 and Kv2.2 in Islets

Xiaoyan (Nina) Li, James Herrington, Aleksandr Petrov, Lan Ge, George Eiermann, Yusheng Xiong, Mette V. Jensen, Hans E. Hohmeier, Christopher B. Newgard, Maria L. Garcia, Michael Wagner, Bei B. Zhang, Nancy A. Thornberry, Andrew D. Howard, Gregory J. Kaczorowski and Yun-Ping Zhou
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 407-416; DOI: https://doi.org/10.1124/jpet.112.199083

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Research ArticleEndocrine and Diabetes

Distinct Roles of Kv2.1 and Kv2.2 in Islets

Xiaoyan (Nina) Li, James Herrington, Aleksandr Petrov, Lan Ge, George Eiermann, Yusheng Xiong, Mette V. Jensen, Hans E. Hohmeier, Christopher B. Newgard, Maria L. Garcia, Michael Wagner, Bei B. Zhang, Nancy A. Thornberry, Andrew D. Howard, Gregory J. Kaczorowski and Yun-Ping Zhou
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 407-416; DOI: https://doi.org/10.1124/jpet.112.199083
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