GPCRs as therapeutic targets for heart disease:
Getting to the heart of the matter

Published on August 14th, 2019

In the heart, GPCR signaling pathways and GRKs determine the pathophysiology of heart disease. It has been shown that increased expression and activity of GRK2 and GRK5 contribute to the loss of contractile reserve in the stressed and failing heart, inhibition of overactive GRKs could be the next therapeutic approach to treat heart failure.


Cardiovascular disease is a term that includes a variety of disorders that affect the heart and its vasculature. The most well-known form of heart disease is coronary heart disease (CHD). CHD is characterized by narrowing blood vessels and atherosclerotic plaque build-up which can lead to myocardial infarction1. The resulting loss of cardiomyocytes leads to an increase in cardiac work, which in turn triggers sympathetic nerve fibers and chromaffin cells from the adrenal medulla to release catecholamines into the heart via the bloodstream2.

β-Adrenergic receptors

These catecholamines can bind to β-adrenergic receptors (β-ARs) which are found on cardiomyocytes, leading to enhanced contractility and promoting cellular hypertrophy in order to meet cardiac demands. At first this adaptation is successful but over time the sustained β-AR activation eventually results in loss of responsiveness to sympathetic signaling, in turn contributing to heart failure.

Adrenergic receptors, such as the β- adrenergic receptors mentioned above, belong to the superfamily of membrane proteins; G protein- coupled receptors or GPCRS. This superfamily contains 800-1000 receptors3 and can be classified into several subclasses based on their sequence homology and functional characteristics4. For more information on the structure of GPCRs, click here.

GPCR structure and binding mechanism

In the inactive state the GPCR intracellular domain is bound to a heterotrimer of guanine nucleotide-binding proteins, comprising a GDP-bound Gα subunit, as well as Gβ and Gγ subunits5.

A representation of a ligand bound to a GPCR, adapted from Pfleger et al., 2019

Figure 1: A representation of a ligand bound to a GPCR, adapted from Pfleger et al., 2019

Once a ligand has bound, the receptor undergoes a conformational change leading to the replacement of GDP with GTP within the Gα subunit. This leads to the dissociation of the heterotrimer from the receptor carboxyl terminus and the detachment of the Gα and Gβγ subunits. The free Gα and Gβγ subunits initiate signaling pathway that mediate a wide range of cellular effects7.

A representation of the disassociation of the the Gα and Gβγ subunits, adapted from Pfleger et al., 2019

Figure 2: A representation of the disassociation of the Gα and Gβγ subunits, adapted from Pfleger et al., 2019

In cardiomyocytes, contractile force, rate and growth are regulated the production of ligands and their signaling effects. Of the 16 Gα mentioned above, there are four major classes: Gs, Gi/o, Gq/11 and G12/13. These subtypes all have different roles to play, for example: Gs -coupled β-ARs (subtype 1 and 2) increase cardiomyocyte contractility8. Whereas Gi-coupled β-ARs (subtype 2) and muscarinic receptors (subtype 2) reduce contractility9.

Therefore, any changes to this balance of GPCR signaling can lead to dysregulation of critical pathways within cardiomyocytes which contribute to the development of cardiovascular disease.

Cardiac G- protein coupled receptor kinases (GKRs)

Desensitization and downregulation of ligand bound GPCRs are predominantly mediated by GRKs. There are seven members that make up the family of serine/threonine kinases; GRK1-GRK7. In the heart, the two most prominent GRKs are GRK2 and GRK510 and are the primary regulators of β1-AR and β2-AR desensitization in response to catecholamines.

In a stressed or failing heart, where there is prolonged catecholamine exposure, the expression and activity of GRK2 and GRK5 are found to be augmented11. This sustained increase in GRK expression is the basis of pathological β-AR insensitivity and reduction which leads to the loss of cardiac contraction and relaxation. The diverse functions of GRKs make them a novel, specific and valuable target for heart failure. In addition it is now being shown that inhibition of the canonical activity of GRKs allows for broader targeting of GPCRs than can be achieved with receptor- specific antagonists.

Targeting GPCRs and GRKs in heart failure

Over the years, several approaches have been used to target GRK2 activity, one of the first and most frequently used approaches involves the use of viral mediated gene delivery systems. Systems such as adenovirus have been used to express a peptide inhibitor that targets GRK2-Gβγ binding6.

The advantage of small-molecule inhibitors is that they do not require virus-mediated gene delivery. It is for this reason that there has been a push to screen random-peptide phage display libraries for small molecules that prevent GRK2-Gβγ binding. This search has led to the identification of M119, a compound that disrupts GPCR-stimulated translocation of GRK2 to the membrane in cardiomyocytes12. M119 has also been shown to prevent cardiac dysfunction, reduce cardiac hypertrophy and block isoprenaline induced GRK2 increase in vivo12.

Likewise, Paroxetine has been identified as a GRK2 binding partner that inhibits agonist-induced β-AR phosphorylation. It also inhibited receptor internalization by binding to the GRK2 active site as opposed to inhibition by binding GRK2 activation through Gβγ binding13.


Considering the crucial role of GRKs in desensitizing β-ARs and impairing cardiac function, there is a real potential for therapeutic strategies to target GRK in a way that reduces the effect of heart failure. In this vein, the search for small molecules could also yield selective compounds that may one day be used to treat heart failure.


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