PT  - JOURNAL ARTICLE
AU  - Juliana Akinaga
AU  - Vanessa Lima
AU  - Luiz Ricardo de Almeida Kiguti
AU  - Flavia Hebeler-Barbosa
AU  - Rocio Alcantara-Hernandez
AU  - J. Adolfo Garcia-Sainz
AU  - Andre Sampaio Pupo
TI  - Differential Phosphorylation, Desensitization and Internalization of α1A Adrenoceptors Activated by Norepinephrine and Oxymetazoline.
AID  - 10.1124/mol.112.082313
DP  - 2013 Jan 30
TA  - Molecular Pharmacology
PG  - mol.112.082313
4099  - http://molpharm.aspetjournals.org/content/early/2013/01/30/mol.112.082313.short
4100  - http://molpharm.aspetjournals.org/content/early/2013/01/30/mol.112.082313.full
AB  - Loss of response upon repetitive drug exposure, i.e. tachyphylaxis, is a particular problem for the vasoconstrictor effects of medications containing oxymetazoline (OXY), a α1-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 α1A-ARs are less phosphorylated, desensitized and internalized upon exposure to the phenethylamines norepinephrine (NE), epinephrine or phenylephrine (PE) than are the α1B and α1D subtypes. However, here we show in HEK-293 cells that the low efficacy agonist OXY induces G protein-coupled receptor kinase 2 (GRK2)-dependent α1A-AR phosphorylation, followed by rapid desensitization and internalization(≈40% internalization after 5 min of stimulation), whereas phosphorylation of α1A-ARs exposed to NE depends to a large extent on PKC activity, is not followed by desensitization and the receptors undergo delayed internalization (≈35% after 60 min of stimulation). Native α1A-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 clear indicative of agonist-directed α1A-AR regulation. OXY shows functional selectivity relative to NE and PE at α1A-ARs leading to significant receptor desensitization and internalization, which is important in view of the therapeutic vasoconstrictor effects of this drug and the varied biological process regulated by α1A-ARs.