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Inhibition of cyclic AMP dependent protein kinase by vanadyl sulfate

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Abstract

Vanadium salts influence the activities of a number of mammalian enzymes in vitro but the mechanisms by which low concentrations of vanadium ameliorate the effects of diabetes in vivo remain poorly understood. The hypothesis that vanadium compounds act by inhibiting protein tyrosine phosphatases has attracted most support. The studies described here further evaluate the possibility that vanadyl sulfate trihydrate (VS) can also inhibit 3′,5′-cyclic adenosine monophosphate (cAMP) dependent protein kinase (PKA). Using conventional assay conditions, VS inhibited PKA only at high concentrations (IC50>400 μM); however, PKA inhibition was seen at dramatically lower concentrations of VS (IC50<10 μM) when sequestration of vanadyl ions was minimized. Vanadyl appears to be the effective PKA inhibitor because sodium orthovanadate did not inhibit PKA and inhibition by vanadyl was abolished by potential chelators such as ethylenediaminetetraacetic acid or glycyl peptides. PKA inhibition by vanadyl appears to be mixed rather than strictly competitive or uncompetitive and may replicate the inhibitory effects of high concentrations of Mg2+. The effect of vanadyl on PKA provides a possible explanation for the effects of vanadium salts on fat tissue lipolysis and perhaps on other aspects of energy metabolism that are controlled by cAMP-dependent mechanisms. Considering the high degree of conservation of the active sites of protein kinases, vanadyl may also influence other members of this large protein family.

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Abbreviations

BMOV:

Bis(maltolato)oxovanadium(IV)

BSA:

Bovine serum albumin

cAMP:

3′,5′-Cyclic adenosine monophosphate

DTT:

Dithiothreitol

EDTA:

Ethylenediaminetetraacetic acid

EGTA:

Ethyleneglycol bis(β-aminoethylether)tetraacetic acid

EPR:

Electron paramagnetic resonance

GSH:

Reduced glutathione

K :

Equilibrium constant

k cat :

Catalytic constant

K i :

Competitive inhibition constant

\( {K}\ifmmode{'}\else$'$\fi_{{\text{i}}} \) :

Uncompetitive inhibition constant

K m :

Michaelis–Menten constant

MES:

2-(N-Morpholino)ethanesulfonic acid

OV:

Sodium orthovanadate

PDE:

Cyclic nucleotide phosphodiesterase

PI3K:

Phosphatidylinositol 3′-OH kinase

PKA:

Cyclic AMP dependent protein kinase

SEM:

Standard error of the mean

STZ:

Streptozotocin

UBC:

University of British Columbia

VS:

Vanadyl sulfate trihydrate

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Acknowledgements

We thank Grant Mauk and Federico Rosell (Department of Biochemistry and Molecular Biology, UBC) for help with EPR spectroscopy and Chris Orvig and Nicholas Aebischer (Department of Chemistry, UBC) for selected EPR studies and the supply of vanadium compounds. Finally, we thank John McNeill and members of his laboratory (Faculty of Pharmaceutical Sciences, UBC) for many helpful discussions. This work was supported by an operating grant from the Canadian Institutes of Health Research (to R.W.B.) and a UBC graduate fellowship (to K.A.J.).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada, V6T 1Z3

    Kioumars A. Jelveh & Roger W. Brownsey

  2. Department Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

    Rachel Zhande

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  1. Kioumars A. Jelveh
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  2. Rachel Zhande
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  3. Roger W. Brownsey
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Correspondence to Roger W. Brownsey.

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Jelveh, K.A., Zhande, R. & Brownsey, R.W. Inhibition of cyclic AMP dependent protein kinase by vanadyl sulfate. J Biol Inorg Chem 11, 379–388 (2006). https://doi.org/10.1007/s00775-006-0087-8

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