Alternative signaling: cardiomyocyte beta1-adrenergic receptors signal through EGFRs

Abstract

Acute stimulation of cardiac beta1-adrenergic receptors (beta1ARs) by norepinephrine represents the strongest endogenous mechanism for increasing cardiac function, but long-term stimulation induces cardiomyocyte apoptosis and contributes to cardiac disease. These effects have been attributed to coupling of the beta1AR to the stimulatory G protein (Gs) and classical cAMP-mediated signaling. In this issue of the JCI, Noma and colleagues report that cardiomyocyte beta1ARs may in addition deliver an antiapoptotic signal through transactivation of EGFRs (see the related article beginning on page 2445). Their findings provide a perspective for a novel class of receptor ligands that may direct beta1AR signaling toward alternative signaling pathways.

Figure 1. β1AR-mediated signal transduction in cardiomyocytes.

Classical ligand-activated βARs enhance cardiac contractility by coupling to G_s, formation of cAMP by adenylyl cyclase (AC), and PKA-dependent phosphorylation of various target proteins (e.g., ryanodine receptor [RyR]; phospholamban [PLN], troponin I [TnI], and the L-type Ca²⁺ channel [LTCC]). Chronic β₁AR stimulation is detrimental and induces cardiomyocyte hypertrophy and apoptosis. In this issue of the JCI, Noma et al. (10) have delineated a novel signaling pathway leading to GRK- and β-arrestin–dependent Src-kinase (SRC) and MMP activation. MMP activation in turn sheds HB-EGF from the cell surface, and this serves as a ligand for cardiomyocyte EGFRs, which mediate ERK/MAPK activation. This pathway protects from β₁AR-induced cardiomyocyte apoptosis but has been associated with cardiac hypertrophy.