RT Journal Article SR Electronic T1 Quantification of Functional Selectivity at the Human α1A-Adrenoceptor JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 298 OP 307 DO 10.1124/mol.110.067454 VO 79 IS 2 A1 Evans, Bronwyn A. A1 Broxton, Natalie A1 Merlin, Jon A1 Sato, Masaaki A1 Hutchinson, Dana S. A1 Christopoulos, Arthur A1 Summers, Roger J. YR 2011 UL http://molpharm.aspetjournals.org/content/79/2/298.abstract AB Although G protein-coupled receptors are often categorized in terms of their primary coupling to a given type of Gα protein subunit, it is now well established that many show promiscuous coupling and activate multiple signaling pathways. Furthermore, some agonists selectively activate signaling pathways by promoting interaction between distinct receptor conformational states and particular Gα subunits or alternative signaling proteins. We have tested the capacity of agonists to stimulate Ca2+ release, cAMP accumulation, and changes in extracellular acidification rate (ECAR) at the human α1A-adrenoceptor. Signaling bias factors were determined by novel application of an operational model of agonism and compared with the reference endogenous agonist norepinephrine; values significantly different from 1.0 indicated an agonist that promoted receptor conformations distinct from that favored by norepinephrine. Oxymetazoline was a full agonist for ECAR and a partial agonist for Ca2+ release (bias factor 8.2) but failed to stimulate cAMP production. Phenylephrine showed substantial bias toward ECAR versus Ca2+ release or cAMP accumulation (bias factors 21 and 33, respectively) but did not display bias between Ca2+ and cAMP pathways. Cirazoline and N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide (A61603) displayed bias toward cAMP relative to Ca2+ release (bias factors of 7.4 and 8.6). It is noteworthy that epinephrine, a second endogenous adrenoceptor agonist, did not display bias relative to norepinephrine. Our finding that phenylephrine displayed significant signaling bias, despite being highly similar in structure to epinephrine, indicates that subtle differences in agonist-receptor interaction can affect conformational changes in cytoplasmic domains and thereby modulate the repertoire of effector proteins that are activated.