Cardiac β 2 adrenergic receptor (AR) dually couples to G s and to pertussis toxin(PTX) sensitive G i proteins ,resulting in opposing effects on cell contractility.Here we show that the coupling preference of β 2AR to the bifurcated signaling pathways,tested over wide ranges of agonist concentrations and receptor densities,is determined by agonist entities.Most β 2AR agonists including zinterol,procaterol or salbutamol activate concurrent G s and G i signaling in both rat and mouse ventricular myocytes,as evidenced by a marked potentiating effect of PTX on contractile responses.Fenoterol,however ,sorts the β 2AR primarily to G s signaling,as evidenced by the lack of effect of PTX.Similar results were observed in transgenic mice overexpressing human β 2AR.In cells from failing rat hearts where the contractile response to zinterol was severely depressed due to an up regulation of G i,fenoterol,which activates G s bypassing the G i signaling pathway,rescued the diminished β 2AR response.Thus,agonist directed sorting of receptor stimulus affords a novel therapeutic strategy to enhance desired “signaling specific”effects while avoiding adverse side effects of therapeutic agents. Cardiac β 2 adrenergic receptor (AR) dually couples to G s and to pertussis toxin (PTX) sensitive G i proteins, resulting in opposing effects on cell contractility. Here we show that the coupling preference of β 2AR to the bifurcated signaling pathways, tested over wide ranges of agonist concentrations and receptor densities, is determined by agonist entities. Host β 2AR agonists including zinterol, procaterol or salbutamol activate concurrent G s and G i signaling in both rat and mouse ventricular myocytes, as evidenced by a marked potentiating effect of PTX on contractile responses. Fenoterol, however, sorts the β 2AR to G s signaling, as evidenced by the lack of effect of PTX. Similar results were observed in transgenic mice overexpressing human β 2AR. In cells from failing rat hearts where the contractile response to zinterol was severely depressed due to an upregulation of G i, fenoterol, which activates G s bypassing the G i signaling pathway, rescued the diminis hed β 2AR response. Triggers, agonist directed sorting of receptor stimulus affords a novel therapeutic strategy to enhance the desirable “signaling specific” effects while preventing adverse effects of therapeutic agents.