Key result
Beta-arrestin-dependent signaling at cardiac GPCRs promotes cardioprotection, suggesting biased ligands for chronic cardiac disease.
Beta-arrestin-mediated signaling at cardiac GPCRs offers cardioprotective effects, suggesting that 'biased ligands' could be a breakthrough treatment for chronic heart disease.
Biased ligands at cardiac GPCRs remain investigational; hypothesis-generating and requires prospective trials before any clinical consideration.
Beta-arrestin is a multifunctional adapter protein well known for its role in G-protein-coupled receptor (GPCR) desensitization. Exciting new evidence indicates that beta-arrestin is also a signaling molecule capable of initiating its own G-protein-independent signaling at GPCRs. One of the best-studied beta-arrestin signaling pathways is the one involving beta-arrestin-dependent activation of a mitogen-activated protein kinase cascade, the extracellular regulated kinase (ERK). ERK signaling, which is classically activated by agonist stimulation of the epidermal growth factor receptor (EGFR), can be activated by a number of GPCRs in a beta-arrestin-dependent manner. Recent work in animal models of heart failure suggests that beta-arrestin-dependent activation of EGFR/ERK signaling by the beta-1-adrenergic receptor, and possibly the angiotensin II Type 1A receptor, are cardioprotective. Hence, a new model of signaling at cardiac GPCRs has emerged and implicates classical G-protein-mediated signaling with promoting harmful remodeling in heart failure, while concurrently linking beta-arrestin-dependent, G-protein-independent signaling with cardioprotective effects. Based on this paradigm, a new class of drugs could be identified, termed "biased ligands", which simultaneously block harmful G-protein signaling, while also promoting cardioprotective beta-arrestin-dependent signaling, leading to a potential breakthrough in the treatment of chronic cardiac disease.
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Patel et al. (2008) conducted a review in Heart failure. Biased ligands targeting beta-arrestin signaling vs. Classical G-protein signaling blockers was evaluated. Beta-arrestin-dependent, G-protein-independent signaling at cardiac GPCRs promotes cardioprotective effects, suggesting that biased ligands could be a novel therapeutic approach for chronic cardiac disease.
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