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

Abstract

Arrestins and G proteins-coupled receptor kinases (GRKs) regulate signaling and trafficking of G protein-coupled receptors. We investigated changes in the expression of arrestins and GRKs in the striatum of patients with Parkinson's disease without (PD) or with dementia (PDD) at post mortem using Western blotting and ribonuclease protection assay. Both PD and PDD groups had similar degree of dopamine depletion in all striatal regions. Arrestin proteins and mRNAs were increased in the PDD group throughout striatum. Protein and mRNA of GRK5, the major subtype in the human striatum, and GRK3 were also upregulated, whereas GRK2 and 6 were mostly unchanged. The PD group had lower concentration of arrestins and GRKs than the PDD group. There was no statistical link between the load of Alzheimer's pathology and the expression of these signaling proteins. Upregulation of arrestins and GRK in PDD may confer resistance to the therapeutic effects of levodopa often observed in these patients. In addition, increased arrestin and GRK concentrations may lead to dementia via perturbation of multiple signaling mechanisms.

Multiple Scaffolding Functions of β-Arrestins in the Degradation of G Protein-coupled Receptor Kinase 2

“…An inverse correlation between GRK2 and arrestin protein levels has also been described in other hypothyroid organs (37) and in macrophages sustainedly stimulated through Toll-like receptors (38). However, a simultaneous increase in GRK2 and ␤-arrestin levels is observed after myocardial infarction (39), in Parkinson disease (40) or during acquisition of analgesic tolerance in the brain (41), indicating that such functional interplay is more complex. Interestingly, up-regulation of GRK2 protein caused by dopamine depletion in animal models of Parkinson disease is reverted upon restoration of receptor signaling with L-dopa treatment (42).…”

Regulation of amygdalar PKA by β-arrestin-2/phosphodiesterase-4 complex is critical for fear conditioning

“…Our earlier work demonstrated that in response to opiate stimulation, ␤-arrestin-1 recruits P300 and activates gene transcription (10). Up-regulation of ␤-arrestin-2 was observed in the striatum of patients of Parkinson's disease with dementia (11). Recent study has revealed that dopaminergic signaling induces the formation of the ␤-arrestin-2-Akt-PP2A complex and thus modulates the effect of lithium in psychiatric disorders (12,13).…”

Rich Tapestry of G Protein-Coupled Receptor Signaling and Regulatory Mechanisms

“…Evolution endowed mammals with ϳ1000 different GPCRs (Römpler et al, 2007) that are phosphorylated by seven GRKs (Moore et al, 2007) and a number of other kinases (Budd et al, 2000;Naik et al, 2005;Luo et al, 2008) and interact with four arrestin subtypes (Gurevich and Gurevich, 2006b). Each tissue and cell has a unique complement of receptors (Penn et al, 2001), GRKs and arrestins (Penn et al, 2001;Gurevich et al, 2002;Ahmed et al, 2008a,b;Bychkov et al, 2008) that changes, sometimes quite dramatically, during development (Gurevich et al, 2002, disease (Ahmed et al, 2008a;Bychkov et al, 2008), and drug treatment (Ahmed et al, 2008b). To make matters even more complicated, phosphorylation of the same receptor at different sites (Pals-Rylaarsdam et al, 1997; Lee et al, 2000;Key et al, 2003;Jones and Hinkle, 2008), by different GRKs Ren et al, 2005;Luo et al, 2008), or even by the same GRK to different levels (Vishnivetskiy et al, 2007) generates functionally distinct receptor species that bind arrestins with different biological consequences.…”