Differential Phosphorylation, Desensitization, and Internalization ofα1A−Adrenoceptors Activated by Norepinephrine and Oxymetazoline

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 a1-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 a1A-ARs are less phosphorylated, desensitized, and internalized on exposure to the phenethylamines norepinephrine (NE), epinephrine, or phenylephrine (PE) than are the a1B and a1D 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 a1A-AR phosphorylation, followed by rapid desensitization and internalization (∼40% internalization after 5 minutes of stimulation), whereas phosphorylation of a1A-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 (∼35% after 60 minutes of stimulation). Native a1A-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 a1A-AR regulation. OXY shows functional selectivity relative to NE and PE at a1A-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 a1A-ARs.

Role for astroglial α1-adrenoreceptors in gliotransmission and control of synaptic plasticity in the neocortex

“…Our finding of desensitization of α1-ARs in astrocytes is in line with data obtained previously in other cell types (Akinaga et al, 2013; Jiang et al, 2013). The apparent desensitization of NA-activated responses upon prolonged exposure to an agonist usually originates from their rapid internalization (Mohan et al, 2013; Akinaga et al, 2013).…”

“…Our finding of desensitization of α1-ARs in astrocytes is in line with data obtained previously in other cell types (Akinaga et al, 2013; Jiang et al, 2013). The apparent desensitization of NA-activated responses upon prolonged exposure to an agonist usually originates from their rapid internalization (Mohan et al, 2013; Akinaga et al, 2013). The common molecular mechanisms of adrenoceptor (as well as many other GPCRs) internalization involve beta-arrestins (Mohan et al, 2013) which have been recently implicated in neurodegenerative diseases (Jiang et al, 2013).…”

“…The common molecular mechanisms of adrenoceptor (as well as many other GPCRs) internalization involve beta-arrestins (Mohan et al, 2013) which have been recently implicated in neurodegenerative diseases (Jiang et al, 2013). The, α1-AR-specific internalization cascade involves PKC, which can be activated by elevations in cytosolic Ca 2+ (Akinaga et al, 2013). Interestingly, the internalization of α1-ARs can also be influenced by their association with the cytoskeleton and lipid rafts (Morris et al, 2008; Akinaga et al, 2013), which can be linked to other astrocytic receptors, for instance P2X1 purinoceptors (Allsopp et al, 2010; Lalo et al, 2011b).…”

“…The, α1-AR-specific internalization cascade involves PKC, which can be activated by elevations in cytosolic Ca 2+ (Akinaga et al, 2013). Interestingly, the internalization of α1-ARs can also be influenced by their association with the cytoskeleton and lipid rafts (Morris et al, 2008; Akinaga et al, 2013), which can be linked to other astrocytic receptors, for instance P2X1 purinoceptors (Allsopp et al, 2010; Lalo et al, 2011b). The possibility of the activation of purinoceptors by autocrine release of ATP from astrocytes might provide feedback to adrenergic signaling.…”

Changes in Adrenoceptors and G-Protein-Coupled Receptor Kinase 2 in <smlcap>L</smlcap>-NAME-Induced Hypertension Compared to Spontaneous Hypertension in Rats

“…Although GRK2 may be involved in the desensitization of α 1 -ARs [39], either the increased GRK2 expression in both the aortas [12] and the MRA of SHR or the decreased GRK2 expression in the aortas of LNHR did not correlate with the changes observed in α 1 -adrenergic mediated responses.…”