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Peptide inhibitors of G protein-coupled receptor kinases

Winstel, R., Ihlenfeldt, H.G., Jung, G., Krasel, C. and Lohse, M.J. (2005) Peptide inhibitors of G protein-coupled receptor kinases. Biochemical Pharmacology, 70 (7). pp. 1001-1008. ISSN 0006-2952

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To link to this article DOI: 10.1016/j.bcp.2005.06.012

Abstract/Summary

G protein-coupled receptor kinases (GRKs) are regulatory enzymes involved in the modulation of seven-transmembrane-helix receptors. In order to develop specific inhibitors for these kinases, we synthesized and investigated peptide inhibitors derived from the sequence of the first intracellular loop of the beta(2)-adrenergic receptor. Introduction of changes in the sequence and truncation of N- and C-terminal amino acids increased the inhibitory potency by a factor of 40. These inhibitors not only inhibited the prototypical GRK2 but also GRK3 and GRK5. In contrast there was no inhibition of protein kinase C and protein kinase A even at the highest concentration tested. The peptide with the sequence AKFERLQTVTNYFITSE inhibited GRK2 with an IC50 of 0.6 mu M, GRK3 with 2.6 mu M and GRK5 with 1.6 mu M. The peptide inhibitors were non-competitive for receptor and ATP. These findings demonstrate that specific peptides can inhibit GRKs in the submicromolar range and suggest that a further decrease in size is possible without losing the inhibitory potency. (c) 2005 Published by Elsevier Inc.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy
ID Code:13607
Uncontrolled Keywords:G-protein-coupled receptor kinases, receptor desensitization, phosphorylation, non-competitive inhibition , LIGHT-DEPENDENT PHOSPHORYLATION, FAILING HUMAN HEART, RHODOPSIN KINASE, SUBSTRATE-SPECIFICITY, PURIFICATION, EXPRESSION, DESENSITIZATION, RESENSITIZATION, SEQUESTRATION, ACTIVATION

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