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β2-adrenoceptor agonists can both stimulate and inhibit glucose uptake in mouse soleus muscle through ligand-directed signalling

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Abstract

The β-adrenoceptor agonists BRL37344 and clenbuterol have opposite effects on glucose uptake in mouse soleus muscle, even though the β2-adrenoceptor mediates both effects. Different agonists may direct the soleus muscle β2-adrenoceptor to different signalling mechanisms. Soleus muscles were incubated with 2-deoxy[1-14C]-glucose, β-adrenoceptor agonists, other modulators of cyclic AMP, and inhibitors of intracellular signalling. The adenylyl cyclase activator forskolin (1 μM), the phosphodiesterase inhibitor rolipram (10 μM) and BRL37344 (10, but not 100 or 1,000, nM) increased, whereas clenbuterol (100 nM) decreased, glucose uptake. Forskolin increased, whereas clenbuterol decreased, muscle cyclic AMP content. BRL37344 (10 nM) did not increase cyclic AMP. Nevertheless, protein kinase A (PKA) inhibitors prevented the stimulatory effect of BRL37344. Nanomolar but not micromolar concentrations of adrenaline stimulated glucose uptake. After preincubation of muscles with pertussis toxin (100 ng/ml), 100 nM clenbuterol, 0.1-10 μM adrenaline and 100 nM BRL37344 stimulated glucose uptake. Clenbuterol increased the proportion of phosphorylated to total β2-adrenoceptor. Inhibitors of phosphatidylinositol 3-kinase (PI3K) and the stress-activated mitogen-activated protein kinase (MAPK), but not of the classical MAPK pathway, prevented stimulation of glucose uptake by BRL37344. Elevation of the cyclic AMP content of soleus muscle stimulates glucose uptake. Clenbuterol, and high concentrations of adrenaline and BRL37344 direct the β2-adrenoceptor partly to Gαi, possibly mediated by β2-adrenoceptor phosphorylation. The stimulatory effect of 10 nM BRL37344 requires the activity of PKA, PI3K and p38 MAPK, consistent with BRL37344 directing the β2-adrenoceptor to Gαs. Ligand-directed signalling may explain why β2-adrenoceptor agonists have differing effects on glucose uptake in soleus muscle.

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Acknowledgments

RAN was supported by a bursary from the Ghanaian government. We thank Julie Cakebread for her work on the manuscript and David Hislop for finalising the figures, and Paul Trayhurn for commenting on the manuscript.

Conflict of interest

J Arch and M Cawthorne consult for various pharmaceutical companies but have no dealings that present any conflict with the results in this paper.

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  1. Robert A. Ngala

    Present address: Department of Molecular Medicine, School of Medical Science, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

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  1. Clore Laboratory, University of Buckingham, Hunter Street, Buckingham, MK18 1EG, UK

    Robert A. Ngala, Jacqueline F. O’Dowd, Claire J. Stocker, Michael A. Cawthorne & Jonathan R. S. Arch

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Ngala, R.A., O’Dowd, J.F., Stocker, C.J. et al. β2-adrenoceptor agonists can both stimulate and inhibit glucose uptake in mouse soleus muscle through ligand-directed signalling. Naunyn-Schmiedeberg's Arch Pharmacol 386, 761–773 (2013). https://doi.org/10.1007/s00210-013-0860-5

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