Deleterious effects on the heart from chronic stimulation of β-adrenergic receptors (βARs), members of the 7 transmembrane receptor family, have classically been shown to result from G s -dependent adenylyl cyclase activation. Here, we identify a new signaling mechanism using both in vitro and in vivo systems whereby β-arrestins mediate β 1 AR signaling to the EGFR. This β-arrestin-dependent transactivation of the EGFR, which is independent of G protein activation, requires the G protein-coupled receptor kinases 5 and 6. In mice undergoing chronic sympathetic stimulation, this novel signaling pathway is shown to promote activation of cardioprotective pathways that counteract the effects of catecholamine toxicity. These findings suggest that drugs that act as classical antagonists for G protein signaling, but also stimulate signaling via β-arrestin-mediated cytoprotective pathways, would represent a novel class of agents that could be developed for multiple members of the 7 transmembrane receptor family.Introduction β-Adrenergic receptors (βARs) belong to the family of 7 transmembrane receptors (7TMRs) (1) and mediate the powerful regulatory effects on cardiac function of the catecholamine neurotransmitters epinephrine and norepinephrine. β 1 ARs constitute more than 70% of the cardiac βARs. Catecholamine stimulation of β 1 ARs results in activation of heterotrimeric G proteins followed by rapid phosphorylation of the receptor, resulting in desensitization (2). Homologous desensitization of β 1 ARs is brought about by phosphorylation of the receptor by G protein-coupled receptor kinases (GRKs), leading to the recruitment of β-arrestin, which then sterically interdicts further coupling to G proteins (3) and targets the receptor for internalization (3). In addition to β-arrestin's role in terminating G protein signaling, recent studies demonstrate that β-arrestins also function as adapter molecules, allowing for the assembly of multiprotein signaling complexes such as ERKs and tyrosine kinases (4, 5). For the angiotensin II type 1A receptor (AT 1A R), this second wave of β-arrestin-mediated signaling has recently been demonstrated to be independent of G protein signaling (6) and to require the activity of GRKs 5 and 6 (7).The signaling mechanisms that underlie the activation of the mitogenic ERK growth response by 7TMRs are complex and likely result from both classical G protein-regulated effectors such as PKA and PKC and non-G protein-mediated crosstalk, such as EGFR transactivation (8). The current paradigm of transactivation involves agonist stimulation of a 7TMR, which through a number of undefined steps leads to MMP-mediated cleavage and

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Positron emission tomography neither confirms nor excludes involvement of the mediastinum in patients with non-small cell lung cancer. Cervical mediastinoscopy with lymph node biopsy remains the criterion standard for mediastinal staging.

The beta-adrenergic receptor (betaAR) signaling system is one of the most powerful regulators of cardiac function and a key regulator of Ca(2+) homeostasis. We investigated the role of betaAR stimulation in augmenting cardiac function and its role in the activation of Ca(2+)/calmodulin-dependent kinase II (CaMKII) using various betaAR knockouts (KO) including beta(1)ARKO, beta(2)ARKO, and beta(1)/beta(2)AR double-KO (DKO) mice. We employed a murine model of left anterior descending coronary artery ligation to examine the differential contributions of specific betaAR subtypes in the activation of CaMKII in vivo in failing myocardium. Cardiac inotropy, chronotropy, and CaMKII activity following short-term isoproterenol stimulation were significantly attenuated in beta(1)ARKO and DKO compared with either the beta(2)ARKO or wild-type (WT) mice, indicating that beta(1)ARs are required for catecholamine-induced increases in contractility and CaMKII activity. Eight weeks after myocardial infarction (MI), beta(1)ARKO and DKO mice showed a significant attenuation in fractional shortening compared with either the beta(2)ARKO or WT mice. CaMKII activity after MI was significantly increased only in the beta(2)ARKO and WT hearts and not in the beta(1)ARKO and DKO hearts. The border zone of the infarct in the beta(2)ARKO and WT hearts demonstrated significantly increased apoptosis by TUNEL staining compared with the beta(1)ARKO and DKO hearts. Taken together, these data show that cardiac function and CaMKII activity are mediated almost exclusively by the beta(1)AR. Moreover, it appears that beta(1)AR signaling is detrimental to cardiac function following MI, possibly through activation of CaMKII.