Differential phosphorylation, desensitization, and internalization of alpha1A-adrenoceptors activated by norepinephrine and oxymetazoline.

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Akinaga J, Lima V, Kiguti LR, Hebeler-Barbosa F, Alcantara-Hernandez R, Garcia-Sainz JA, Pupo AS

Differential phosphorylation, desensitization, and internalization of alpha1A-adrenoceptors activated by norepinephrine and oxymetazoline.

Mol Pharmacol. 2013 Apr;83(4):870-81. doi: 10.1124/mol.112.082313. Epub 2013 Jan 30.

PubMed ID

23364786 [ View in PubMed

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Abstract

Loss of response on repetitive drug exposure (i.e., tachyphylaxis) is a particular problem for the vasoconstrictor effects of medications containing oxymetazoline (OXY), an alpha1-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 alpha1A-ARs are less phosphorylated, desensitized, and internalized on exposure to the phenethylamines norepinephrine (NE), epinephrine, or phenylephrine (PE) than are the alpha1B and alpha1D 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 alpha1A-AR phosphorylation, followed by rapid desensitization and internalization ( approximately 40% internalization after 5 minutes of stimulation), whereas phosphorylation of alpha1A-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 ( approximately 35% after 60 minutes of stimulation). Native alpha1A-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 alpha1A-AR regulation. OXY shows functional selectivity relative to NE and PE at alpha1A-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 alpha1A-ARs.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Oxymetazoline	Alpha-1B adrenergic receptor	Protein	Humans	Unknown	Agonist	Details
Oxymetazoline	Alpha-1D adrenergic receptor	Protein	Humans	Unknown	Agonist	Details