Kinase Activity Is Not Required for G Protein-Coupled Receptor Kinase 4 Restraining mTOR Signaling during Cilia and
Julian Gerhards1, Lars D Maerz2, Edda S F Matthees3
1Section of Pharmacogenomics, Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Eberhard-Karls-University Tübingen, Tübingen, Germany.
Journal of the American Society of Nephrology : JASN
|February 22, 2023
Summary
G protein-coupled receptor kinase 4 (GRK4) regulates kidney development and cilia formation independently of its kinase activity. Hypertension-associated GRK4 variants may cause disease through elevated mTOR signaling, not hyperactivity.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- G protein-coupled receptor kinase 4 (GRK4) influences blood pressure by regulating renal sodium excretion.
- GRK4 genetic variants are inconsistently linked to hypertension, despite showing increased kinase activity.
- The role of GRK4 in cellular signaling and kidney development remains largely uncharacterized.
Purpose of the Study:
- Investigate the role of GRK4 in kidney development and cellular signaling.
- Determine the mechanism by which GRK4 variants contribute to hypertension.
- Elucidate the relationship between GRK4, cilia function, and mTOR signaling.
Main Methods:
- Utilized zebrafish models with GRK4 depletion to observe kidney development.
- Employed human fibroblasts and murine kidney spheroid models to study GRK4's cellular effects.
- Assessed the impact of wild-type and kinase-dead GRK4, as well as hypertension-associated variants, on cellular phenotypes.
Main Results:
- GRK4 depletion in zebrafish led to kidney dysfunction, glomerular cysts, and elongated cilia.
- GRK4 knockdown in human and murine models also resulted in elongated primary cilia.
- Kinase-dead GRK4 rescued these phenotypes, while hypertension-associated variants did not, implicating a non-kinase function and elevated mTOR signaling.
Conclusions:
- GRK4 regulates kidney development and cilia formation through a mechanism independent of its kinase activity.
- Hypertension-associated GRK4 variants are dysfunctional, leading to impaired ciliogenesis and potentially altered mTOR signaling.
- These findings reveal a novel role for GRK4 in kidney development and cilia biology, distinct from its previously understood function in blood pressure regulation.
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