β-Adrenergic Receptor-PI3K Signaling Crosstalk in Mouse Heart: Elucidation of Immediate Downstream Signaling Cascades

Abstract

Sustained β-adrenergic receptors (βAR) activation leads to cardiac hypertrophy and prevents left ventricular (LV) atrophy during LV unloading. The immediate signaling pathways downstream from βAR stimulation, however, have not been well investigated. The current study was to examine the early cardiac signaling mechanism(s) following βAR stimulation. In adult C57BL/6 mice, acute βAR stimulation induced significant increases in PI3K activity and activation of Akt and ERK1/2 in the heart, but not in lungs or livers. In contrast, the same treatment did not elicit these changes in β1/β2AR double knockout mice. We further showed the specificity of β2AR in this crosstalk as treatment with formoterol, a β2AR-selective agonist, but not dobutamine, a predominantly β1AR agonist, activated cardiac Akt and ERK1/2. Acute βAR stimulation also significantly increased the phosphorylation of mTOR (the mammalian target of rapamycin), P70S6K, ribosomal protein S6, GSK-3α/β (glycogen synthase kinase-3α/β), and FOXO1/3a (the forkhead box family of transcription factors 1 and 3a). Moreover, acute βAR stimulation time-dependently decreased the mRNA levels of the muscle-specific E3 ligases atrogin-1 and muscle ring finger protein-1 (MuRF1) in mouse heart. Our results indicate that acute βAR stimulation in vivo affects multiple cardiac signaling cascades, including the PI3K signaling pathway, ERK1/2, atrogin-1 and MuRF1. These data 1) provide convincing evidence for the crosstalk between βAR and PI3K signaling pathways; 2) confirm the β2AR specificity in this crosstalk in vivo; and 3) identify novel signaling factors involved in cardiac hypertrophy and LV unloading. Understanding of the intricate interplay between β2AR activation and these signaling cascades should provide critical clues to the pathogenesis of cardiac hypertrophy and enable identification of targets for early clinical interaction of cardiac lesions.

Deletion of MLIP (Muscle-enriched A-type Lamin-interacting Protein) Leads to Cardiac Hyperactivation of Akt/Mammalian Target of Rapamycin (mTOR) and Impaired Cardiac Adaptation

“…As previously reported (27)(28)(29), ISO treatment resulted in increased activity of mTOR, as evidenced by the increase in phospho-mTOR to total mTOR ratio in ISOtreated Mlip ϩ/ϩ when compared with saline-treated Mlip ϩ/ϩ hearts (Fig. 6F).…”

Pathophysiology of Takotsubo Syndrome

“…42 Interestingly, it has been reported that β2AR-Gi signaling can modulate the cellular PI3K/AKT pathways, indicating a mechanistic link between catecholamine stress and metabolic defects in TTS. 43,44 This provides some clinical evidence to support the hypothesis that TTS may be cardioprotective against the toxic storm of catecholamines; the medium term prognosis of TTS is reasonable (subject to surviving the acute phase without serious complications), despite the propensity for cardiogenic shock and other acute complications, suggesting potential protection mechanisms being activated in the heart. The Gi activation in the first 30 min could lead to AKT activation.…”

Information Thermodynamics Derives the Entropy Current of Cell Signal Transduction as a Model of a Binary Coding System

“…Informational thermodynamics for analyzing dynamic biochemical networks and systems biology have also been developed to assess the cell response to external stimuli [1][2][3][4][5][6]. In addition, in in vivo analysis, a significant amount of data on signal transduction has accumulated, and the quantitative analysis of a network of signaling cascades can be performed using new technology [7][8][9][10][11][12][13][14][15][16]. In this study, a quantitative evaluation theory of a signaling cascade is described from the source coding theory of a binary code system applied for biological signal transduction.…”

“…External stimulation on the cell induces a concentration fluctuation in the phosphorylation of the signaling molecules. More specifically, a fluctuation in the signaling molecules' concentration tentatively increases, followed by a decrease over a long duration, τ j , of several hours [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] (Figure 1). Here, we defined the occurrence probability, p j and p j * , which represents the selection probability of j-th step using X j or X j *, respectively:…”