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Protein histidine [de]phosphorylation in insulin secretion: abnormalities in models of impaired insulin secretion

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Abstract

In the majority of cell types, including the islet β-cell, transduction of extracellular signals involves ligand binding to a receptor, often followed by the activation G proteins and their effector modules. The islet β-cell is unusual in that glucose lacks an extracellular receptor. Instead, events consequent to glucose metabolism promote insulin secretion via the generation of diffusible second messengers and mobilization of calcium. A selective increase in intracellular calcium has been shown to regulate the phosphorylation status key islet proteins thereby facilitating insulin secretion. In addition to classical protein kinases [e.g., protein kinases A and C], recent studies from our laboratory have focused on the expression and function of various forms of NDPK/nm23-like histidine kinases in clonal β-cells, normal rodent, and human islets. Further, we recently reported localization of a cytosolic protein histidine phosphatase [PHP] in INS 832/13 cells, normal rat islets, and human islets. siRNA-mediated knock down of nm23-H1 and PHP in insulin-secreting INS 832/13 cells significantly attenuated glucose-induced insulin secretion. We also observed significant alterations in the expression and function of nm23-H1/PHP in β-cells chronically exposed to elevated levels of glucose and saturated fatty acids, such as palmitate (i.e., glucolipotoxicity). Similar changes were also noted in islets from the Goto-Kakizaki and Zucker Diabetic Fatty rats, two known models for type 2 diabetes. It is concluded that protein histidine phosphorylation–dephosphorylation cycles play novel regulatory roles in G protein-mediated physiological insulin secretion and that abnormalities in this signaling axis lead to impaired insulin secretion in glucolipotoxicity and type 2 diabetes.

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Notes

  1. In siRNA-mediated knock down of nm23-H1 studies, we used a pool of three duplexes. The sequences for those duplexes are duplex A: sense, GGAAAGAAGUGAUCACAAAtt and antisense, UUUGUGAUCACUUCUUUCCtt; duplex B: sense, GAACAAUUCUCCAACCUAUtt and antisense, AUAGGUUGGAGAAUUGUUCtt; and duplex C: sense, GUAGCUAAUCUCUU-GUGUUtt and antisense, AACACAAGAGAU-UAGCUACtt [all sequences are provided in 5′ → 3′ orientation; purchased from Santa Cruz Biotechnology, Santa Cruz, CA].

Abbreviations

ACL:

ATP-citrate lyase

CER:

Ceramide

GSIS:

Glucose-stimulated insulin secretion

GK rat:

Goto-Kakizaki rat

H4-HK:

Histone 4 phosphorylating histidine kinase

IMPDH:

Inosine monophosphate dehydrogenase

MPA:

Mycophenolic acid

NDPK:

Nucleoside diphosphate kinase

Nox:

Phagocyte-like NADPH oxidase

PHP:

Protein histidine phosphatase

ROS:

Reactive oxygen species

ZDF rat:

Zucker diabetic fatty rat

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Acknowledgements

This research was supported by a Merit Review Award from the Department of Veterans Affairs and the National Institutes of Health [DK 74921]. AK is also the recipient of the Senior Research Career Scientist Award from the Department of Veterans Affairs.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University and β-Cell Biochemistry Laboratory, John D. Dingell VA Medical Center, Detroit, MI, 48201, USA

    Anjaneyulu Kowluru

  2. Institute for Pharmacology and Medicinal Chemistry, Westfalische Wilhelms University, Münster, Germany

    Susanne Klumpp & Josef Krieglstein

  3. Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, 259 Mack Avenue, Detroit, MI, 48201, USA

    Anjaneyulu Kowluru

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  1. Anjaneyulu Kowluru
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  2. Susanne Klumpp
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  3. Josef Krieglstein
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Correspondence to Anjaneyulu Kowluru.

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This article is dedicated to the late Dr. Susanne Klumpp for her pioneering contributions to the field of protein histidine [de]phosphorylation in cellular signal transduction.

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Kowluru, A., Klumpp, S. & Krieglstein, J. Protein histidine [de]phosphorylation in insulin secretion: abnormalities in models of impaired insulin secretion. Naunyn-Schmiedeberg's Arch Pharmacol 384, 383–390 (2011). https://doi.org/10.1007/s00210-011-0616-z

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