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Regulation of glycogen synthase activation in isolated hepatocytes

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Abstract

Glycogen synthase, the regulatory enzyme of glycogen synthesis undergoes multisite phosphorylation leading to its inactivation. The kinases responsible for this covalent modification (ex. cAMP-dependent protein kinase, protein kinase C and glycogen synthase kinase-3) are controlled by the second messengers generated by different hormones. The isolated hepatocytes has been used as one of the experimental models for studying this complex regulatory process. Inactivation of glycogen synthase by glucagon and vasopressin has been shown to be accompanied with incorporation of phosphate into the enzyme protein. Insulin has been shown to activate glycogen synthase by inhibition of kinases and activation of synthase phosphatase. Glycogen synthase is activated by several gluconeogenic substrates, in addition to glucose. Studies in hepatocytes with activators and inhibitors of protein kinase C show that this enzyme negatively controls glycogen synthase. The differential effects of the phosphatase inhibitors, calyculin A and okadaic acid in liver cells provide supporting evidence that protein phosphatase type-1 plays a major role in the regulation of glycogen synthase. Hepatocytes isolated from diabetic rats of both types (insulin-dependent and non-insulin-dependent) mimic the defective glycogen synthase activation seenin vivo.

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Abbreviations

cAMP:

cyclic 3′, 5′ adenosine monophosphate

ADP:

adenosine diphosphate

G-6-P:

glucose-6-phosphate

GSK-3:

glycogen synthase kinase-3

IDDM:

insulin-dependent diabetes mellitus

NIDDM:

non-insulin-dependent diabetes mellitus

PKA:

cAMP-dependent protein kinase

PKC:

protein kinase C

PMA, TPA:

4β-phorbol 12β-myristate 13α-acetate

PP-1, PP-2A:

protein phosphatases (type 1 and 2A)

UTP:

uridine triphosphate

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  1. Department of Biochemistry, University of Saskatchewan, 107 Wiggins Road, S7N 5E5, Saskatoon, Saskatchewan, Canada

    Subbiah Pugazhenthi & Ramji L. Khandelwal

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  1. Subbiah Pugazhenthi
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  2. Ramji L. Khandelwal
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Pugazhenthi, S., Khandelwal, R.L. Regulation of glycogen synthase activation in isolated hepatocytes. Mol Cell Biochem 149, 95–101 (1995). https://doi.org/10.1007/BF01076568

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