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Design of substrates and inhibitors of G protein-coupled receptor kinase 2 (GRK2) based on its phosphorylation reaction

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Abstract

The G protein-coupled receptor kinase (GRK) family consists of seven cytosolic serine/threonine (Ser/Thr) protein kinases, and among them, GRK2 is involved in the regulation of an enormous range of both G protein-coupled receptors (GPCRs) and non-GPCR substrates that participate in or regulate many critical cellular processes. GRK2 dysfunction is associated with multiple diseases, including cancers, brain diseases, cardiovascular and metabolic diseases, and therefore GRK2-specific substrates/inhibitors are needed not only for studies of GRK2-mediated cellular functions but also for GRK2-targeted drug development. Here, we first review the structure, regulation and functions of GRK2, and its synthetic substrates and inhibitors. We then highlight recent work on synthetic peptide substrates/inhibitors as promising tools for fundamental studies of the physiological functions of GRK2, and as candidates for applications in clinical diagnostics.

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Acknowledgements

We thank Ms. Shigemi Terakubo and Ms. Niño Nakajima (St. Marianna University School of Medicine) for technical support. This work was supported by JSPS KAKENHI grant number 17K08254 and AMED under Grant Number JP19hm0102067.

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Authors and Affiliations

  1. Division of Biopharmaceutics and Pharmacokinetics, National Cerebral and Cardiovascular Center Research Institute, 6-1 Shinmachi, Kishibe, Suita, Osaka, 564-8565, Japan

    Jeong-Hun Kang

  2. Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorigaoka, Ikeda, Osaka, 563-8577, Japan

    Riki Toita

  3. AIST-Osaka University Advanced Photonics and Biosensing Open Innovation Laboratory, AIST, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Riki Toita

  4. Center for Advanced Medical Innovation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Takahito Kawano & Masaharu Murata

  5. Department of Microbiology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, 216-8511, Japan

    Daisuke Asai

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  1. Jeong-Hun Kang
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  2. Riki Toita
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Kang, JH., Toita, R., Kawano, T. et al. Design of substrates and inhibitors of G protein-coupled receptor kinase 2 (GRK2) based on its phosphorylation reaction. Amino Acids 52, 863–870 (2020). https://doi.org/10.1007/s00726-020-02864-x

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