A Cellular Gβγ Antagonist, GRK2i



GRK2i, a GRK2 inhibitory polypeptide, specifically inhibits Gβγ activation of GRK2. It corresponds to the Gβγ-binding domain and acts as a cellular Gβγ antagonist.

Pharmacologic action

Gβγ has the effect on the termination of G protein-coupled receptor signal transduction, by mediating the membrane translocation/activation of the P-adrenergic receptor kinases (βARK1 and βARK2). The synthetic GRK2 inhibitory peptide (GRK2i) corresponds to Gβγ-binding domain of GRK2 and specifically inhibits Gβγ activation of GRK2 in neurons, which inhibited GRK2 phosphorylation in βarr-2 k.o. mice.


The studies in heterologous expression systems suggest that GRK2i does not interact with GRK3, 5 or 6, even it is not 100% determined that the effect of GRK2i is completely specific for GRK2. Furthermore, there was no disruption of GRK3 function, when the same concentration of GRK2i was introduced into other neurons. Heterologous expression studies have indicated that co-expression of GRK2, -3, or -5 with βarr-2 can produce agonist dependent acute MOR desensitization. Thus, it remains possible that the GRK3 or 5 contribute to the small residual desensitization remaining after blocking both ERK1/2 and GRK2 in neurons from w.t. mice. Besides, treatment with GRK2i could not completely inhibit the EGF induced enhanced migration of Gβ3s cells, and there was some degree of scratch wound healing.

Pharmacokinetics and metabolism

The effect of GRK2i inhibiting the activation of G-protein-coupled receptor kinase 2 (GRK2) was tested. Via the recording pipette for >50 mins, the neurons were "dialyzed" with GRK2i (10 μM). And after the recording pipette with or without GRK2i obtained access to the cell, dobutamine (100 μM) was added to the bath for 50 mins. With the presence of GRK2i in the pipette solution, the dobutamine-dependent inward current was significantly smaller (−39.0 ± 4.1 pA, n = 7, p = 0.0136, unpaired t-test) than the control current (−55.0 ± 2.5 pA, n = 5), when GRK2i was absent from the pipette solution. When applied alone, the inhibitors (GRK2i, n = 7, p = 0.6262) had no significant influence on the resting membrane potential.


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4. Macrez, N., Morel, J. L., Kalkbrenner, F., Viard, P., Schultz, G., & Mironneau, J. (1997). A βγ dimer derived from G13 transduces the angiotensin AT1 receptor signal to stimulation of Ca2+ channels in rat portal vein myocytes. Journal of Biological Chemistry, 272(37), 23180-23185.

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