GRK5, short for G protein-coupled receptor kinase 5, is a serine/threonine kinase that belongs to the family of GPCR kinases. It is responsible for regulating G protein-coupled receptors (GPCRs), which are crucial for extracellular signal transduction and mammalian physiology. GRK5 can translocate to the nucleus under certain conditions, interacting with non-GPCR-related proteins and DNA to promote non-canonical signaling, including gene transcription [2].

GRK5 deficiency has been associated with several disease conditions. GRK5 knockout (GRK5KO) mice naturally develop mild cognitive impairment (MCI) during aging, suggesting a role in Alzheimer's disease (AD) pathogenesis as MCI is a prodromal stage of AD [1]. In the context of renal fibrosis, GRK5 was significantly overexpressed, and it regulated the HDAC5/Smad3 signaling pathway, indicating its potential as a therapeutic target for treating renal fibrosis [3]. In the heart, genetic deletion of GRK5 in cardiac fibroblasts inhibited angiotensin II-mediated fibroblast activation, leading to decreased fibrosis and cardiac hypertrophy after certain injuries [4].

In conclusion, GRK5 is a multifunctional protein involved in regulating GPCR-related and non-GPCR-related signaling. Model-based research, especially using GRK5KO mouse models, has revealed its significance in neurodegenerative diseases like AD, renal fibrosis, and cardiac diseases such as fibrosis and hypertrophy. Understanding GRK5's functions provides potential therapeutic targets for these chronic degenerative diseases.

References:

1. Suo, William Z. . GRK5 Deficiency Causes Mild Cognitive Impairment due to Alzheimer's Disease. In Journal of Alzheimer's disease : JAD, 85, 1399-1410. doi:10.3233/JAD-215379. https://pubmed.ncbi.nlm.nih.gov/34958040/

2. Marzano, Federica, Rapacciuolo, Antonio, Ferrara, Nicola, Koch, Walter J, Cannavo, Alessandro. 2021. Targeting GRK5 for Treating Chronic Degenerative Diseases. In International journal of molecular sciences, 22, . doi:10.3390/ijms22041920. https://pubmed.ncbi.nlm.nih.gov/33671974/

3. Xiang, Huiling, Huang, Jing, Song, Anni, Xiong, Jing, Zhang, Chun. . GRK5 promoted renal fibrosis via HDAC5/Smad3 signaling pathway. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 38, e23422. doi:10.1096/fj.202301595RRR. https://pubmed.ncbi.nlm.nih.gov/38206179/

4. Eguchi, Akito, Coleman, Ryan, Gresham, Kenneth, Chuprun, J Kurt, Koch, Walter J. . GRK5 is a regulator of fibroblast activation and cardiac fibrosis. In Proceedings of the National Academy of Sciences of the United States of America, 118, . doi:10.1073/pnas.2012854118. https://pubmed.ncbi.nlm.nih.gov/33500351/