Atypical β-adrenoceptor pharmacology described in BJP paper

17 July 2008

Studies by Robert Ngala and colleagues undertaken in the Clore Laboratory, University of Buckingham, UK, on β-adrenoceptor stimulated glucose uptake and fatty acid oxidation in skeletal muscle are reported in British Journal of Pharmacology.

They report that picomolar concentrations of the β3-selective agonist BRL37344 and the β2-selective agonist clenbuterol stimulate glucose uptake in soleus muscle and the C2C12 muscle cell line. The muscle cell line expresses mRNA for β2- but not β1- or β3-adrenoceptors and the β2-adrenoceptor is also the predominant receptor in soleus muscle. However, the effect of 10pM BRL37344 was not sensitive to a β2-adrenoceptor antagonist, or indeed to β1- or β3-antagonists. This suggests that the β2-adrenoceptor can display a novel pharmacology or that a different receptor mediates the response to very low doses of BRL37344 and clenbuterol.

A 1000-fold higher concentration of BRL37344 also stimulated glucose uptake, whereas a similar concentration of clenbuterol inhibited glucose uptake. Both of these effects appear to be mediated by the β2-adrenoceptor. This is an example of two agonists causing different changes in the conformation of a receptor so that they affect different signalling pathways, that is there is ‘ligand directed signalling’.

The full reference is:

Ngala RA, O’Dowd J, Wang SJ, Agarwal A, Stocker C, Cawthorne MA, Arch JRS. Metabolic responses to BRL37344 and clenbuterol in soleus muscle and C2C12 cells via different atypical pharmacologies and β2-adrenoceptor mechanisms. Br J Pharmacol. e-pub ahead of print 16 June 2008. doi:10.1038/bjp.2008.244