The Myocardium-protective Gly-49 Variant of the β1-Adrenergic Receptor Exhibits Constitutive Activity and Increased Desensitization and Down-regulation

Levin, Malin; Marullo, Stéfano; Muntaner, O; Andersson, Bert; Magnusson, Yvonne

doi:10.1074/jbc.m200681200

Cited by 216 publications

(171 citation statements)

References 30 publications

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“…The Ser49Gly polymorphism with a minor allele frequency of 22% has been demonstrated to modulate receptor sensitivity [23]. In clinical studies, variation in the amino acid residue at this location has been shown to influence resting heart rate and survival in a small heart failure cohort [24,25].…”

Section: -Ar Polymorphismsmentioning

confidence: 99%

Genomics, heart failure and sudden cardiac death

Darbar

2008

Heart Fail Rev

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Sudden cardiac death (SCD) is among the most common causes of death in developed countries throughout the world. Despite decreased overall cardiac mortality, SCD vrates appear to be increasing in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. This unfavorable trend is a consequence of our inability to identify those who will die suddenly from lethal ventricular arrhythmias and to develop effective therapies for all populations at risk. The known risk factors for SCD lack the predictive power needed to generate preventive strategies for the large number of fatal arrhythmic events that occur among lowerrisk subsets of the population. Even among recognized high-risk subsets, prediction of SCD remains challenging. With the exception of the implantable cardioverter defibrillator (ICD) there are few effective strategies for the prevention and treatment of SCD. This article discusses the prospect of genomic science as an approach to the identification of patients at high-risk for SCD. While the final common pathway for SCD is malignant ventricular arrhythmias, there are many potential contributors, pathways, and mechanisms by which common genetic variants (polymorphisms) could affect initiation and propagation of life-threatening cardiac arrhythmias. Recent advances in genomic medicine now provide us with novel approaches to both identify candidate genes/pathways and relatively common polymorphisms which may predispose patients to increased risk for SCD. Improved understanding of the relationship between common polymorphisms and SCD will not only improve risk stratification such that ICDs can be targeted to those patients most likely to benefit from them but also provide new insight into the pathophysiology of SCD. KeywordsSudden cardiac death; Genomics; Heart failure; Single nucleotide polymorphisms Heart failure and SCD Heart failure (HF) afflicts approximately 5 million people in the United States, with 550,000 new cases reported annually, but as the population ages both the incidence and prevalence is expected to rise [1]. HF is associated with high mortality and is reportedly responsible for 300,000 deaths annually in the US [1]. Prior to advent of neuro-hormonal antagonists, the mean duration of survival after onset of HF was 1.7 years for men and 3.2 years for women, with only half of patients still alive after 5 years of onset [2]. The two modes of death in patients with HF are circulatory failure due to progressive left ventricular (LV) dysfunction associated with gradual worsening of symptoms, or sudden cardiac death (SCD) in relatively clinically stable patients [3].Although the proportion of sudden deaths in published trials varies significantly, probably due to varying interpretations of reported modes of death, clinical trials data suggests that SCD accounts for approximately one-third of all HF deaths [4]. Epidemiologic evidence from the Framingham heart study suggests that about one-half of all deaths due to HF occur...

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Section: -Ar Polymorphismsmentioning

confidence: 99%

Genomics, heart failure and sudden cardiac death

Darbar

2008

Heart Fail Rev

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“…The two subtypes have been directly compared by heterologously expressing each in the same cell line. ␤ 1 AR is more resistant to agonist-mediated downregulation than ␤ 2 AR in CHW (25)(26)(27) and HEK 293 cells (28) and in some studies, undergoes up-regulation in the latter cells (29,30).…”

mentioning

confidence: 99%

Resistance of the Human β1-Adrenergic Receptor to Agonist-mediated Down-regulation

Liang

Austin²,

Hoang

et al. 2003

Journal of Biological Chemistry

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Prolonged agonist stimulation results in down-regulation of most G protein-coupled receptors. When we exposed baby hamster kidney cells stably expressing the human ␤ 1 -adrenergic receptor (␤ 1 AR) to agonist over a 24-h period, we instead observed an increase of ϳ30% in both ␤ 1 AR binding activity and immune-detected receptors. In contrast, ␤ 2 AR expressed in these cells exhibited a decrease of >50%. We determined that the basal turnover rates of the two subtypes were similar (t1 ⁄2 ϳ 7 h) and that agonist stimulation increased ␤ 2 AR but not ␤ 1 AR turnover. Blocking receptor trafficking to lysosomes with bafilomycin A 1 had no effect on basal turnover of either subtype but blocked agonist-stimulated ␤ 2 AR turnover. As ␤ 1 AR mRNA levels increased in agonist-stimulated cells, ␤ 1 AR up-regulation appeared to result from increased synthesis with no change in degradation. To explore the basis for the subtype differences, we expressed chimeras in which the C termini had been exchanged. Each chimera responded to persistent agonist stimulation based on the source of its C-tail; ␤ 1 AR with a ␤ 2 AR C-tail underwent down-regulation, and ␤ 2 AR with a ␤ 1 AR C-tail underwent up-regulation. The C-tails had a corresponding effect on agonist-stimulated receptor phosphorylation and internalization with the order being ␤ 2 AR > ␤ 1 AR with ␤ 2 AR C-tail > ␤ 2 AR with a ␤ 1 AR C-tail > ␤ 1 AR. As internalization may be a prerequisite for down-regulation, we addressed this possibility by co-expressing each subtype with arrestin-2. Although ␤ 1 AR internalization was increased to that of ␤ 2 AR, down-regulation still did not occur. Instead, ␤ 1 AR accumulated inside the cells. We conclude that in unstimulated cells, both subtypes appear to be turned over by the same mechanism. Upon agonist stimulation, both subtypes are internalized, and ␤ 2 AR but not ␤ 1 AR undergoes lysosomal degradation, the fate of each subtype being regulated by determinants in its C-tail.

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“…For example in the human β 1 -adrenoceptor Ser49Gly, a SNP located in the N-terminus, displays a distinct trafficking phenotype (57) with the variant exhibiting increased basal and agoniststimulated adenylyl cyclase activity as well as enhanced agonist-induced downregulation (58). For the β 2 -adrenoceptor the picture is more complex with an Arg16Gly variant receptor displaying enhanced agonist-promoted downregulation whilst a Gln27Glu polymorphism is resistant to degradation (reviewed in (59).…”

Section: The Integrity Of the Pdz-binding Motif Of The P2y 12 R Is Esmentioning

confidence: 99%

Pathophysiological consequences of receptor mistraffic: Tales from the platelet P2Y 12 receptor

Cunningham

Aungraheeta

Mundell

2017

Molecular and Cellular Endocrinology

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The Myocardium-protective Gly-49 Variant of the β1-Adrenergic Receptor Exhibits Constitutive Activity and Increased Desensitization and Down-regulation

Cited by 216 publications

References 30 publications

Genomics, heart failure and sudden cardiac death

Genomics, heart failure and sudden cardiac death

Resistance of the Human β1-Adrenergic Receptor to Agonist-mediated Down-regulation

Pathophysiological consequences of receptor mistraffic: Tales from the platelet P2Y 12 receptor

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