The Janus faces of adrenoceptors: Factors controlling the coupling of adrenoceptors to multiple signal transduction pathways

1. The adrenoceptors; (AR) are an important subfamily of rhodopsin-like G-protein-coupled receptors that couple to an increasingly large number of signalling mechanisms. Two important factors that determine the pathways that are used are the C-terminal region of the receptor and the agonist used to activate the receptor. 2. Studies of splice variants of the mouse beta(3)-AR showed that the C-terminus is a factor controlling the signalling characteristics. Although these receptors differ only at the C-terminus, the beta(3b)-AR coupled to both G(s) and G(i), whereas the beta(3a)-AR coupled solely to G(s). 3. Examination of four splice variants of the human alpha(1a)-AR showed that all were able to couple to pertussis toxin-sensitive G-proteins, even though they have radically different C-terminal regions. 4. Comparison of the effects of the beta(3)-AR ligands CL316243 and SR59230A showed that both can activate the mouse beta(3)-AR but that SR59230A uses pathways other than cAMP accumulation in 3T3-F442A cells. 5. Examination of a series of alpha(1)-AR agonists for their ability to activate a number of signalling pathways revealed that A61603 acted as a full agonist in all assays, whereas oxymetazoline was unable to cause cAMP accumulation, suggesting agonist-selective signalling at the human alpha(1A)-AR.