Functional antagonism of different G protein-coupled receptor kinases for β-arrestin-mediated angiotensin II receptor signaling

Abstract

␤-arrestins bind to G protein-coupled receptor kinase (GRK)-phosphorylated seven transmembrane receptors, desensitizing their activation of G proteins, while concurrently mediating receptor endocytosis, and some aspects of receptor signaling. We have used RNA interference to assess the roles of the four widely expressed isoforms of GRKs (GRK 2, 3, 5, and 6) in regulating ␤-arrestinmediated signaling to the mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK) 1͞2 by the angiotensin II type 1A receptor. Angiotensin II-stimulated receptor phosphorylation, ␤-arrestin recruitment, and receptor endocytosis are all mediated primarily by GRK2͞3. In contrast, inhibiting GRK 5 or 6 expression abolishes ␤-arrestin-mediated ERK activation, whereas lowering GRK 2 or 3 leads to an increase in this signaling. Consistent with these findings, ␤-arrestin-mediated ERK activation is enhanced by overexpression of GRK 5 and 6, and reciprocally diminished by GRK 2 and 3. These findings indicate distinct functional capabilities of ␤-arrestins bound to receptors phosphorylated by different classes of GRKs.angiotensin receptor ͉ extracellular signal-regulated kinase ͉ phosphorylation ͉ small interfering RNA

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

“…Manipulations of GRK2/3 concentrations have the opposite effects. So far, this functional antagonism has been demonstrated for two GPCRs, angiotensin II receptor [54] and V2 vasopressin receptor [92], and only in cultured cells. It is unclear to what extent these findings are applicable to the in vivo situation in general and to neuronal signaling mechanisms in particular.…”

“…Therefore, changes in the concentration of GRKs modulate arrestin-mediated signaling. Different subclasses of GRKs have differential role in arrestin-dependent cellular functions [54,92]. GRK2 and 3 largely mediate "classic" GRK functions, such as receptor phosphorylation, arrestin recruitment, and receptor endocytosis.…”

“…Conversely, in vivo studies suggest that receptors may be preferentially phosphorylated by specific GRKs [26,44,45,57,95] and interact with specific arrestins [58,78]. Importantly, GPCRs phosphorylated by different GRKs may signal differently [54,92]. Thus, signaling via GPCRs may be differentially regulated by the changes in the cellular complement of arrestins and GRKs.…”

Antagonistic sensory cues generate gustatory plasticity in Caenorhabditis elegans

“…(B) Expression of mec-4d/mec-2 constructs in the ASI neurons, in the ASH/ADL nociceptive neurons or the ASH neurons significantly impaired gustatory plasticity (Po0.01). (Perry and Lefkowitz, 2002;Kim et al, 2005;Ren et al, 2005). The C. elegans genome contains two GRKs, grk-1 and grk-2, and one arrestin gene, arr-1 (Fukuto et al, 2004).…”

Processive phosphorylation: Mechanism and biological importance

“…This has been demonstrated for the angiotensin II type 1A receptor, where arrestin proteins have a role in transducing signals independent of G proteins. RNA interference experiments showed that the signaling consequences of arrestin-receptor binding depended on which GRK isoform was responsible for phosphorylating the receptor [36]. Thus, GRK2 and GRK3 were primarily responsible for receptor endocytosis, while GRK5 and GRK6 were required for arrestinmediated ERK activation.…”