G protein-coupled receptor kinases (GRKs) are serine/threonine protein kinases best known for their ability to phosphorylate activated G protein-coupled receptors. Numerous studies have revealed that GRKs are important regulators of normal cell and organism function and contribute to a number of human diseases including cardiovascular disease, cancer and neurological disorders. While there has been significant progress in understanding GRK function, the mechanistic basis for many of the in vivo functions of GRKs remains largely unknown. During the last grant period, we initiated studies on the two C. elegans GRKs and found that they regulate a number of important biological processes including egg-laying, growth and sex determination. Interestingly, our work revealed that GRK-2 regulates serotonin metabolism and that GRK-1 and GRK-2 mediate opposing effects on egg-laying. Moreover, the serotonin metabolite 5-HIAA was found to bind to SER-1, a 5-HT2A receptor ortholog, and oppose the effects of serotonin. To further define the biological role of GRKs and provide mechanistic insight into how GRK structure correlates with in vivo function, we propose to use molecular, biochemical and cell biological strategies to better define the mechanistic basis for GRK regulation of egg-laying. Our central hypothesis is that these studies will enable us to mechanistically link GRK structure/function with important biological processes in the worm and that our findings will provide novel insight relevant to understanding the physiological and pathophysiological role of GRKs in humans. We plan to test our central hypothesis by pursuing three specific aims.
In aim 1, we will elucidate the mechanisms involved in GRK-2 regulation of egg-laying and test the hypotheses that: (A) GRK-2 regulates serotonin metabolism by regulating vesicular monoamine transporter and/or monoamine oxidase activity and (B) 5-HIAA functions as a biased SER-1 agonist.
In aim 2, we will elucidate the mechanisms involved in GRK-1 regulation of egg-laying and test the hypothesis that GRK-1 stimulates Go signaling.
In aim 3, we will use molecular and proteomic strategies to define the in vivo interactions and substrates for C. elegans GRKs. We are poised to mechanistically dissect how GRK-2 regulates serotonin metabolism, how serotonin and 5-HIAA differentially modulate serotonin receptor function and how GRK-1 and GRK-2 coordinately regulate biology. These studies will provide important insight that is highly relevant to not only understanding GRKs in the worm but also to understanding how GRKs function in humans.

Public Health Relevance

GRKs are important regulators of normal organism function and contribute to a number of human diseases including cardiovascular disease, cancer and various neurological disorders. The proposed research is relevant to public health and the NIH mission because it will elucidate the mechanisms involved in GRK function in vivo and thereby provide important insight into the pathophysiological role of GRKs in humans.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Dunsmore, Sarah
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Thomas Jefferson University
Schools of Medicine
United States
Zip Code
Chaturvedi, Madhu; Schilling, Justin; Beautrait, Alexandre et al. (2018) Emerging Paradigm of Intracellular Targeting of G Protein-Coupled Receptors. Trends Biochem Sci 43:533-546
Komolov, Konstantin E; Benovic, Jeffrey L (2018) G protein-coupled receptor kinases: Past, present and future. Cell Signal 41:17-24
Luo, Jiansong; Busillo, John M; Stumm, Ralf et al. (2017) G Protein-Coupled Receptor Kinase 3 and Protein Kinase C Phosphorylate the Distal C-Terminal Tail of the Chemokine Receptor CXCR4 and Mediate Recruitment of ?-Arrestin. Mol Pharmacol 91:554-566
Wang, Jianjun; Luo, Jiansong; Aryal, Dipendra K et al. (2017) G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans. J Biol Chem 292:5943-5956
Komolov, Konstantin E; Du, Yang; Duc, Nguyen Minh et al. (2017) Structural and Functional Analysis of a ?2-Adrenergic Receptor Complex with GRK5. Cell 169:407-421.e16
DeRita, Rachel M; Zerlanko, Brad; Singh, Amrita et al. (2017) c-Src, Insulin-Like Growth Factor I Receptor, G-Protein-Coupled Receptor Kinases and Focal Adhesion Kinase are Enriched Into Prostate Cancer Cell Exosomes. J Cell Biochem 118:66-73
Komolov, Konstantin E; Bhardwaj, Anshul; Benovic, Jeffrey L (2015) Atomic Structure of GRK5 Reveals Distinct Structural Features Novel for G Protein-coupled Receptor Kinases. J Biol Chem 290:20629-47
Kang, Dong Soo; Tian, Xufan; Benovic, Jeffrey L (2014) Role of ?-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking. Curr Opin Cell Biol 27:63-71
Carr 3rd, Richard; Du, Yang; Quoyer, Julie et al. (2014) Development and characterization of pepducins as Gs-biased allosteric agonists. J Biol Chem 289:35668-84
Quoyer, Julie; Janz, Jay M; Luo, Jiansong et al. (2013) Pepducin targeting the C-X-C chemokine receptor type 4 acts as a biased agonist favoring activation of the inhibitory G protein. Proc Natl Acad Sci U S A 110:E5088-97

Showing the most recent 10 out of 126 publications