Authors:

Kathryn P McCauley

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About Paper:

G-protein coupled receptor kinases (GRKs) desensitize activated GPCRs via phosphorylation at the plasma membrane, allowing beta-arrestin recruitment and internalization. There are seven human GRKs (GRK1-7) in the body. GRK2 and GRK5 are abundantly expressed in cardiovascular tissue, implicating them in cardiovascular diseases. Here we focus on GRK5. Increased activity of GRK5 has been shown to increase the risk of cardiovascular diseases. In addition, recent studies show increased GRK5 activity in relation to failing human myocardium and its over-expression in the heart leading to reduced cardiac B-AR responsiveness. Inhibitor BARKct improves failing tissue function by inhibiting GRK5 binding to the beta-gamma G-protein subunits to prevent internalization of the receptor. Other studies show that GRK5 is localized to the centrosome and involved in regulating cell cycle progression, but GRK5 can also phosphorylate cell cycle regulators such as nucleophosmin (NPM1) and p53, leading to altered cell cycle activity and higher risk of cancer. In this study we tested GRK5 inhibitors using kinase assays with radioactive phosphate isotope (P-32) to test the potency of a series of inhibitors at different concentrations to determine potency and compare to GRK2 to determine selectivity. In future we aim to obtain the structure of GRK5 bound to these inhibitors using cryo-electron microscopy to better understand their interactions. This study will aid rational based drug design for cardiovascular diseases and cancer, widening the scope of our understanding of the mode of inhibition of these inhibitors. Keywords: GRK; Cardiovascular; Cancer; Inhibitor; Kinase

Source:

Purdue University / 2024

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Co-authors:

Kathryn P McCauley