Physiological consequences of β-adrenergic receptor disruption

Rohrer, Daniel K.

doi:10.1007/s001090050278

Cited by 42 publications

(24 citation statements)

References 61 publications

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“…In contrast to the ␤ 1 AR knockout mice, gene disruption of the ␤ 2 AR does not appear to significantly alter cardiac physiology (Rohrer, 1998). This suggests that, under normal conditions, the ␤ 2 AR plays no major role in murine cardiac physiology.…”

Section: The ␤ 2 Armentioning

confidence: 84%

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The Adrenergic Pathway and Heart Failure

Keys

Koch²

2004

Recent Progress in Hormone Research

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Heart failure represents the endpoint to many triggering cardiovascular pathologies. However, there are molecular and biochemical features that remain common to the failing heart, despite the varying etiologies. Principal among these is heightened activation of the sympathetic nervous system and associated enhancement of adrenergic signaling pathways via the catecholamines, norepinephrine and epinephrine. During heart failure, several hallmark alterations in the adrenergic system contribute to loss of cardiac function. To specifically study these changes in a physiologically relevant setting, we and others have utilized advances in genetically engineered mouse technology. This chapter will discuss the many transgenic and knockout mouse models that have been developed to study the adrenergic system in the normal and failing heart. These models include genetically manipulated alterations of adrenergic receptors, linked heterotrimeric G proteins, and the regulatory G proteincoupled receptor kinases (GRKs). Among the more-interesting information gained from these models is the finding that inhibition of a particular GRK -GRK2 or ␤ adrenergic receptor kinase 1 (␤ARK1) -is a potential novel therapeutic strategy to improve function in the setting of heart failure. Furthermore, we will discuss recent transgenic research that proposes an important role for hypertension in the development of heart failure. Overall, genetically engineered mouse models pertaining to this critical myocardial signaling system have provided novel insight into heart function under normal conditions and during states of dysfunction and failure.

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Section: The ␤ 2 Armentioning

confidence: 84%

“…These mice recently have been reviewed in detail (Rohrer, 1998). Although surviving ␤ 1 AR knockout mice have normal heart rates, their response to exercise is abrogated (Rohrer et al, 1996).…”

Section: The ␤ 1 Armentioning

confidence: 99%

The Adrenergic Pathway and Heart Failure

Keys

Koch²

2004

Recent Progress in Hormone Research

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“…For many of these receptors as well as their signaling proteins, knockout as well as transgenic mice are available. This is especially the case for ␤-ARs and their signaling molecules, because of their predominant role in mediating cardiac hypertrophic diseases (43, 104,114,150,162,170,171). Because of the prominent role of these receptors in mediating autonomic effects, these are discussed more extensively.…”

Section: Adrenergic Nervesmentioning

confidence: 99%

Autonomic control of blood pressure in mice: basic physiology and effects of genetic modification

Janssen

Smits

2002

American Journal of Physiology-Regulatory, Integrative and Comp

106

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Control of blood pressure and of blood flow is essential for maintenance of homeostasis. The hemodynamic state is adjusted by intrinsic, neural, and hormonal mechanisms to optimize adaptation to internal and environmental challenges. In the last decade, many studies showed that modification of the mouse genome may alter the capacity of cardiovascular control systems to respond to homeostatic challenges or even bring about a permanent pathophysiological state. This review discusses the progress that has been made in understanding of autonomic cardiovascular control mechanisms from studies in genetically modified mice. First, from a physiological perspective, we describe how basic hemodynamic function can be measured in conscious conditions in mice. Second, we focus on the integrative role of autonomic nerves in control of blood pressure in the mouse, and finally, we depict the opportunities and insights provided by genetic modification in this area.

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“…Catecholaminergic stimulation of the heart increases both heart rate and contractility (1). The essential role of β-ARs in the stress-induced enhancement of cardiac function has been demonstrated using β 1 -AR knockout mice that are unable to develop normal responses to stress (2). However, the complexity of the β-AR signaling cascade has made it difficult to elucidate specific contributions of downstream targets to the physiologic responses to stress.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice

Shan¹,

Kushnir²,

et al. 2010

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During the classic "fight-or-flight" stress response, sympathetic nervous system activation leads to catecholamine release, which increases heart rate and contractility, resulting in enhanced cardiac output. Catecholamines bind to β-adrenergic receptors, causing cAMP generation and activation of PKA, which phosphorylates multiple targets in cardiac muscle, including the cardiac ryanodine receptor/calcium release channel (RyR2) required for muscle contraction. PKA phosphorylation of RyR2 enhances channel activity by sensitizing the channel to cytosolic calcium (Ca 2+ ). Here, we found that mice harboring RyR2 channels that cannot be PKA phosphorylated (referred to herein as RyR2-S2808A +/+ mice) exhibited blunted heart rate and cardiac contractile responses to catecholamines (isoproterenol). The isoproterenol-induced enhancement of ventricular myocyte Ca 2+ transients and fractional shortening (contraction) and the spontaneous beating rate of sinoatrial nodal cells were all blunted in RyR2-S2808A +/+ mice. The blunted cardiac response to catecholamines in RyR2-S2808A +/+ mice resulted in impaired exercise capacity. RyR2-S2808A +/+ mice were protected against chronic catecholaminergic-induced cardiac dysfunction. These studies identify what we believe to be new roles for PKA phosphorylation of RyR2 in both the heart rate and contractile responses to acute catecholaminergic stimulation. IntroductionDuring exercise, heart rate (chronotropy) and cardiac contractility (inotropy) increase to meet the metabolic demands of the organs. Stress-induced activation of the sympathetic nervous system (SNS) results in catecholamine release, stimulation of β-adrenergic receptors (β-ARs), generation of cAMP, and activation of cAMP-dependent protein kinase (PKA) in cardiac myocytes. Catecholaminergic stimulation of the heart increases both heart rate and contractility (1). The essential role of β-ARs in the stress-induced enhancement of cardiac function has been demonstrated using β 1 -AR knockout mice that are unable to develop normal responses to stress (2). However, the complexity of the β-AR signaling cascade has made it difficult to elucidate specific contributions of downstream targets to the physiologic responses to stress.β-AR stimulation and downstream activation of PKA enhances calcium (Ca 2+ ) signaling in myocytes (3). During excitation-contraction (EC) coupling in the heart, depolarization of the sarcolemmal membrane activates the voltage-gated calcium channel (Ca V 1.2), causing a small Ca 2+ influx into the cell. This in turn triggers the opening of ryanodine receptor/calcium release channel (RyR2) and the release of Ca 2+ from the sarcoplasmic reticu-

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Physiological consequences of β-adrenergic receptor disruption

Cited by 42 publications

References 61 publications

The Adrenergic Pathway and Heart Failure

The Adrenergic Pathway and Heart Failure

Autonomic control of blood pressure in mice: basic physiology and effects of genetic modification

Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice

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