Altered Beta-adrenergic Receptor Gene Regulation and Signaling in Chronic Heart Failure

β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice

“…The receptors signal by increasing the activity of stimulatory guanine nucleotidebinding proteins (G proteins), thereby increasing the activity of PKA (Farfel et al 1999). Chronic or overstimulation of the adrenergic pathways adversely affects myocyte growth and function, produces hypertension (Port and Bristow 2001;Taylor and Bristow 2004), and is a prognostic indicator in heart failure (Esler et al 1997). Mouse models of chronically enhanced β1AR, G protein, and protein kinase PKA activity suffer from increased mortality and decreased resistance to stress (see discussion in Yan et al 2007).…”

β-adrenoceptor blocker treatment and the cardiac β-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure

“…It is now generally accepted that, in the failing human heart, β-1 AR are decreased, β-2 AR may or may not be decreased but are uncoupled from the effector system adenylyl cyclase, the amount and activity of G s -protein is unchanged, the amount and activity of G i -protein is increased as is the amount and activity of the G-protein-coupled receptor kinase (GRK); on the other hand, activities of adenylyl cyclase and protein kinase A are unchanged (for reviews, see Brodde and Michel 1999;Port and Bristow 2001;Lohse et al 2003). The consequence of these changes is a reduction in cardiac β-AR functional responsiveness.…”

Pharmacogenetics of the human beta-adrenergic receptors

“…For the cardiovascular system, ADRBs mediate alterations in myocardial metabolism, heart rate and systolic and diastolic function. 5,6 In general, agonist binding increases cardiac contractile strength, relaxation and heart rate with acute changes observed within seconds of agonist release. Indeed, the prompt responses mediated through activation of ADRBs are critical to regulation of circulatory homeostasis and to the survival of the organism (e.g.…”

“…Chronic stimulation of adrenergic pathways is harmful and inhibits myocyte growth and function. 6 Persistent stimulation of ADRBs leads to downregulation of ADRB signaling by decreasing receptor sensitivity to catecholamines and by increasing inhibitory G protein (G i ) activity. 7 In chronic heart failure for instance, catecholamines are elevated, leading to tonic adrenergic signaling; this increased level of cardiac adrenergic drive is an important prognostic indicator in heart failure.…”

“…5 Stimulation of G s also directly activates effectors, such as the L-type calcium channel. 6 The importance of the ADRB system in cardiovascular physiology has been explored on multiple levels and led to the discovery of multiple polymorphic variants in this system ( Figure 1). 14,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] ADRB1 polymorphisms Twenty-three polymorphisms of ADRB1 have been described and 13 of these predict amino-acid changes in the ADRB1 protein.…”