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G-Protein Coupled Receptor Kinases - Key Regulators of GPCR Signalling
G-protein coupled receptors (GPCRs) detect extracellular signals and transmit them into the cell by activating intracellular G-proteins. These G-proteins then further pass on the signal to other proteins which leads to a cellular response.
A plethora of biological functions like vision, taste, cognition, pain perception, chemotaxis of immune cells, cytokine release, fibrosis and tissue remodelling, heart rate and contractility, and vascular tone are regulated by GPCR signalling.
To prevent cell overstimulation, activated GPCRs are marked by phosphorylation of their intracellular domain. This important step is carried out by G- protein-coupled receptor kinases (GRKs). There are seven GRKs known.
Phosphorylated GPCRs attract a class of proteins called β-arrestins which pull the receptor inside the cell for deactivation.
Canonical Activity of GRKs - Acute Effects
Phosphorylation of GPCRs leading to β-arrestin recruitment and receptor internalization is often referred to as the canonical activity of GRKs. (1) It is important for the acute regulation of GPCR activity. When there is high exposure of an external stimulus, GRK activity leads to exhaustion of the receptor on the cell surface and thus to a loss of function.
Non-canonical Activity of GRKs - Chronic Effects
Some GRKs regulate additional cellular processes through the phosphorylation of intracellular targets. Under chronic up-regulation of GRKs, these non-canonical activities may lead to pathophysiological conditions. (1)
For instance, GRK5 can translocate to the nucleus where it can promote pathological gene expression by acting as a histone deacetylase (HDAC) kinase, contributing to maladaptive cardiac remodeling.
GRK5 as a Key Player in Takotsubo Cardiomyopathy
Source: Lecturio.com
Takotsubo cardiomyopathy (TTC) is a life-threatening condition characterised by elevated levels of circulating catecholamines, triggered by severe emotional or physical stress. While TTC mimics the symptoms of myocardial infarction (MI), it manifests itself as severe left ventricular (LV) systolic dysfunction. The left ventricle is unable to contract and adopts the shape of a Japanese octopus pot called tako-tsubo, thus the name. (1, 2, 3)
Both MI and TTC show comparable short-term mortality rates (5-8%). (3,4)
Although the acute symptoms may normalize over days, about 20% of TTC patients show persistent cardiac dysfunction with a high burden of morbidity and increased long-term mortality (17% over 5 years). (5, 6)
There is no evidence-based treatment for patients with TTC.
“Overall, it appears that the search for appropriate life-saving medication after
Takotsubo syndrome is only beginning and has yet to be realized”. (7)
Preclinical Evidence for GRK5 inhibitors as a Treatment Option for Takotsubo Cardiomyopathy
In a mouse model of acute epinephrin-induced Takotsubo syndrome, a single treatment with a prototypic GRK5 inhibitor rapidly improved LV ejection fraction, both short term (1 h) and up to 5 days. (8)
In mice, prototypical GRK5 inhibitors (9) and (conditional) knock-outs (10, 11, 12, 13) improved longterm survival, heart function, cardiac hypertrophy and fibrosis in the transverse aortic constriction (TAC) pressure overload-induced cardiac hypertrophy model.
GRK5 Inhibitors – A Breakthrough Approach for Heart Diseases
GRK5 inhibitors have potential in patients with diverse acute and chronic cardiomyopathies. As shown in animal models, GRK5 inhibitors can restore cardiac function, prevent maladaptive cardiac remodeling and development of heart failure, and reduce morbidity and mortality.
We want to discover and develop GRK5 inhibitors as a first-in-class treatment for acute and chronic Takotsubo cardiomyopathy. In addition, GRK5 inhibitors may represent novel treatment options for other cardiomyopathies.
References
(1) Traynham et al. J. Mol. Cell. Cardiol. 92(2016)196
(2) Lyon et al. J. Am. Coll. Cardiol. 7(2021)902
(3) Movahed et al. J. Am. Heart Assoc. 14(2025)e037219
(4) Uribarri et al. J. Am Heart Assoc. 8(2019)e013701
(5) Akhtar et al. Cardiovasc. Res. 119(2023)1480
(6) Singh et al. Circulation 145(2022)1002
(6) Rudd et al. JACC Adv. 3(2024)100797
(8) Berger et al. 90. Jahrestagung der Deutschen Gesellschaft für Kardiologie – Herz- und Kreislaufforschung e.V. (German Cardiac Society)
Clin. Res. Cardiol. (2024), Link to DGK Annual Meeting 2024
(9) Klöcker et al. 90. Jahrestagung der Deutschen Gesellschaft für Kardiologie – Herz- und Kreislaufforschung e.V. (German Cardiac Society)
Clin. Res. Cardiol. (2024), Link to DGK Annual Meeting 2024
(10) de Lucia et al. Cardiovasc. Res. 118(2022)169
(11) Hullmann et al. Circulation Res. 115(2014)976
(12) Coleman et al. Sci. Signal. 14(2021)eabb5968
(13) Eguchi et al. PNAS USA, 118(2021)e2012854118