Number above the structures indicate amino acid residue numbers of human GRKs based on (Lodowski et al., 2006). All GRKs have a short N-terminal region (green), which is implicated in GPCR binding, followed by RGS homology (RH) domain (magenta). This N-terminal region is unique to the GRK family of kinases. The RH domain is interrupted by the catalytic domain shared by all kinases (dark yellow). These elements are shared by the GRK2/3 and GRK4/5/6 subfamilies. The defining feature of the GRK2/3 subfamily is a C-terminal pleckstrin homology (PH) domain (blue) implicated in binding anionic phospholipids and Gβγ. Members of GRK4/5/6 subfamily use alternative mechanisms for membrane targeting, which include palmitoylation [palmitoylation sites are shown for GRK6A (Jiang et al., 2007)], patches of positively charged residues [amphipathic helix motifs (Thiyagarajan et al., 2004; Jiang et al., 2007) are shown as green boxes; N-terminal basic patches (Pitcher et al., 1996; Boguth et al., 2010) are shown as red boxes], and, in case of visual subtypes, prenylation (C-terminal prenylation sites in GRK1 and 7 are shown as red triangles). Residues Arg106 and Asp110 in GRK2/3, among others, are important for binding Gα_q, a function unique to this subfamily. The position of the key lysine responsible for catalysis in the kinase domain is shown. Mutations K220R in GRK2 and 3, as well as K216M/K217M (Sallese et al., 2000b) in GRK4, K415 in GRK5 (Tiruppathi et al., 2000), and K215M/K216M in GRK 6(Lazari et al., 1999) yield kinase-dead GRKs. The blue box shows the position of the nuclear localization signal (NLS) in GRK5 (residues 388–395) (Johnson et al., 2004). Splice variants of GRK 4 (GRK4β, GRK4γ, and GRK4δ) are produced by in-frame deletion of exon 2 (GRK4β), exon 15 (GRK4γ), or both (GRK4δ (Premont et al., 1996; Sallese et al., 1997; Premont et al., 1999) (gene structure is shown under GRK4 protein; the exons not used in all splice variants are shown in blue) GRK6 splice variants are produced by a frame shift in the C-terminus resulting in a completely different C-terminal sequence in GRK6B as compared to GRK6A and in premature transcription termination in GRK6C (Premont et al., 1999). To generate GRK6A, exon 16 starts two nucleotides downstream, as compared to the longest variant GRK6B, resulting in a frame shif. An alternative upstream exon 16 encoding one amino acid before the stop codon is used to generate GRK6C (respective exons are labeled Exon 16A, Exon 16B, and Exon 16C). In the C-termini of GRK6 splice variants amphipathic helix residues are shown in blue and palmitoylated cysteine in red. Note the lack of palmitoylation sites in GRK6B or GRK6C.

Normal regulation of receptor sensitivity involves receptor phosphorylation by a GRK followed by high affinity binding of an arrestin. Arrestin mediates receptor internalization via coated pits followed by either receptor recycling or degradation. In some pathological cases such as heart failure, an upregulation of one or more GRK isoforms can occur. Increased GRK availability leads to receptor hyper-phosphorylation, facilitated receptor desensitization, internalization, and, ultimately, excessive degradation. Similar effect might be achieved when a GRK with a polymorphism yielding higher activity is expressed. Such a pathological phenotype might be rescued by expression of a GRK inhibitor. Here the use of βARKct is shown, which competes with GRK2 and 3 for Gβγ, thus impeding GRK recruitment to active receptors. Alternatively, GRK knockdown could be used.

In some pathological cases exemplified by L-DOPA-induced dyskinesia, a reduced activity of one or more GRK isoforms seems to be the culprit resulting in supersensitivity of dopaminergic receptors to dopamine stimulation. A defect in receptor desensitization and/or trafficking is evidenced by persistence of D1 dopamine receptors at the plasma membrane, whereas in control animals the receptors are internalized upon L-DOPA administration (Guigoni et al., 2007; Ahmed et al., 2010). The deficiency in GRK function need not necessarily be due to reduced expression, but might stem from insufficient GRK availability in the face of increased demand. In case of dyskinesia, human patients with Parkinson’s disease or animals with experimental parkinsonism are treated with L-DOPA, which produces surges of dopamine in the brain putting pressure on regulatory signaling mechanisms. Overexpression of an appropriate GRK (e.g., GRK6A was successfully used for L-DOPA-induced dyskinesia (Ahmed et al., 2010)] might relieve that pressure by facilitating receptor desensitization and normal trafficking. Alternatively, positive allosteric modulators of GRKs might be developed. L-DOPA-induced dyskinesia is a good example of a condition where simply shutting down signaling by inhibiting dopamine receptors is not an option, because that would defeat the purpose of L-DOPA treatment, which is to provide dopaminergic stimulation to relieve akinesia in Parkinson’s patients. In contrast, using GRK as a target allows for judicial reduction in dopaminergic signaling that alleviates dyskinesia while preserving therapeutic activity of the drug.