BtBs seminar - G Protein-Coupled Receptor Kinase-2: A Potential Therapeutic Target for Cardiovascular Diseases

Gizem Kayki Mutlu, Ankara University, Faculty of Pharmacy, Department of Pharmacology, Tandogan, TURKEY

G protein-coupled receptor kinase 2 (GRK2) is known for its primary role in desensitizing G protein-coupled receptors (GPCRs). It phosphorylates agonist-bound GPCRs resulting in receptor desensitization and internalization. However, under pathological conditions, the expression and activity of GRK2 are upregulated, exacerbating the loss of contractility.  

In addition to its well-established canonical role, noncanonical roles of GRK2 have been emerged in recent years. Due to its multiple binding sites, GRK2 engages in an expansive non-GPCR ‘interactome’. Among these interacting partners, heat shock protein 90 (Hsp90) holds a distinctive role, acting as a chaperone that guides GRK2 to the mitochondria, where it exerts deleterious negative effects. Following ischemic and oxidative stress, extracellular signal-regulated kinases (ERK) phosphorylate GRK2 at the Ser670 residue, facilitating its interaction with hsp90 and its subsequent translocation to the mitochondria. On the other hand, GRK2 undergoes regulation through various post-translational modifications, with S-nitrosylation (SNO) being one of them. This modification involves the binding of NO to cysteine molecules within GRK2, particularly at the C340 residue, which subsequently leads to the inhibition of the kinase. In pathological conditions, the regulation of GRK2 through SNO is disrupted, resulting in GRK2 overactivity. Hence, the significance of this regulatory modification is substantial.   

In the broader context, given the growing body of research on the role of elevated GRK2 levels on cardiac dysfunction, it is not surprising that GRK2 inhibition has been suggested as a potential therapeutic option for cardiac disease. Pharmacological or genetic inhibition of this kinase stands as one of the most promising therapeutic strategies against cardiac diseases in recent years. Ongoing research will highly likely unveil effective options, potentially targeting specific domains, cellular localizations, or non-canonical substrates of the kinase. In this presentation, latest data on GRK2 will be discussed, focusing on its multifaceted roles in both normal and diseased hearts, along with its therapeutic potential as a target.

Ospite: Antonio Zaza

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LINK per partecipare al seminario:  https://unimib.webex.com/unimib-it/j.php?MTID=maf9febb87d97b8d63cede5944ac00a3e

password:  day14 (32914 da telefoni e sistemi video)

Il seminario è APERTO a tutti.

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