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 beta3-AR showed that the C-terminus is a factor controlling the signalling characteristics. Although these receptors differ only at the C-terminus, the beta3b-AR coupled to both Gs and Gi, whereas the beta3a-AR coupled solely to Gs. 3. Examination of four splice variants of the human alpha1A-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 beta3-AR ligands CL316243 and SR59230A showed that both can activate the mouse beta3-AR but that SR59230A uses pathways other than cAMP accumulation in 3T3-F442A cells. 5. Examination of a series of alpha1-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 alpha1A-AR.
Summers
Roger J
RJ
Molecular Pharmacology Laboratory, Department of Pharmacology, Monash University, Clayton, Victoria, Australia. roger.summers@med.monash.edu.au
Broxton
Natalie
N
Hutchinson
Dana S
DS
Evans
Bronwyn A
BA
D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D011941:Receptors, Adrenergic / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*
D018663:Adrenergic Agents; D011941:Receptors, Adrenergic; D022702:Receptors, Adrenergic, beta-3