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Akinaga, Juliana; Lima, Vanessa; de Almeida Kiguti, Luiz Ricardo; Hebeler-Barbosa, Flavia; Alcantara-Hernandez, Rocio; Adolfo Garcia-Sainz, J; Pupo, Andre Sampaio (2013)


Mol. Pharmacol. 83(4):870-881
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Loss of response on repetitive drug exposure (i.e., tachyphylaxis) is a particular problem for the vasoconstrictor effects of medications containing oxymetazoline (OXY), an alpha 1-adrenoceptor (AR) agonist of the imidazoline class. One cause of tachyphylaxis is receptor desensitization, usually accompanied by phosphorylation and internalization. It is well established that alpha 1A-ARs are less phosphorylated, desensitized, and internalized on exposure to the phenethylamines norepinephrine (NE), epinephrine, or phenylephrine (PE) than are the alpha 1B and alpha 1D subtypes. However, here we show in human embryonic kidney-293 cells that the low-efficacy agonist OXY induces G protein-coupled receptor kinase 2-dependent alpha 1A-AR phosphorylation, followed by rapid desensitization and internalization (similar to 40% internalization after 5 minutes of stimulation), whereas phosphorylation of alpha 1A-ARs exposed to NE depends to a large extent on protein kinase C activity and is not followed by desensitization, and the receptors undergo delayed internalization (similar to 35% after 60 minutes of stimulation). Native alpha 1A-ARs from rat tail artery and vas deferens are also desensitized by OXY, but not by NE or PE, indicating that this property of OXY is not limited to recombinant receptors expressed in cell systems. The results of the present study are clearly indicative of agonist-directed alpha 1A-AR regulation. OXY shows functional selectivity relative to NE and PE at alpha 1A-ARs, leading to significant receptor desensitization and internalization, which is important in view of the therapeutic vasoconstrictor effects of this drug and the varied biologic process regulated by alpha 1A-ARs.