Future G protein-coupled receptor targets for treatment of heart failure

Heart failure (HF) still poses an enormous clinical challenge, as its incidence, morbidity, and mortality rates are continuously rising. G protein-coupled receptors (GPCRs) constitute the most ubiquitous superfamily of plasma membrane receptors and represent the single most important type of therapeutic drug target. Because there is overstimulation of the failing heart by various endogenous ligands, such as catecholamines and angiotensin II - which by activating their cognate GPCRs in cardiac muscle induce detrimental effects - therapeutic targeting of these receptors has been pursued. This research has led to the development of successful and useful drug classes, such as angiotensin-converting enzyme inhibitors and α-adrenergic receptor blockers. However, there still is a need to develop innovative treatments that might be more effective at reversing compromised myocyte function. Over the past several years, much evidence has accumulated indicating that a single GPCR, activated by the same endogenous ligand, can elicit several different signaling pathways with quite different, and often opposite, cellular effects. Because the aforementioned ligands, currently used for HF, target these receptors on their extracellular interface, thus merely preventing the endogenous agonists from binding the receptor, they inhibit all the signaling pathways elicited by the receptor indiscriminately. Importantly, several of these pathways emanating from the same GPCR can actually be beneficial for therapy, so their enhancement rather than their blockade is desirable for HF therapy. This highlights the need for selective targeting of GPCR-induced signaling pathways on the intracellular interface of the receptor, which might produce new and innovative therapies for cardiovascular disease.