Peptide inhibitors of G protein-coupled receptor kinases

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• 作者：Rainer Winstel ; Hans-Georg Ihlenfeldt ; Gü ; nther Jung ; Cornelius Krasel and Martin J. Lohse
• 关键词：G-protein-coupled receptor kinases ; Receptor desensitization ; Phosphorylation ; Non-competitive inhibition
• 刊名：Biochemical Pharmacology
• 出版年：2005
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：2005
• 卷：70
• 期：7
• 页码：1001-1008
• 文件大小：297 K

摘要

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 β₂-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 μM, GRK3 with 2.6 μM and GRK5 with 1.6 μM. 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.