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Impaired Adrenergic/Protein Kinase A Response of Slow Delayed Rectifier Potassium Channels as a Long QT Syndrome Motif: Importance and Unknowns.
Policarová, M, Novotný, T, Bébarová, M
The Canadian journal of cardiology. 2019;(4):511-522
Abstract
The slow delayed rectifier potassium current (IKs) significantly contributes to cardiac repolarization under specific conditions, particularly at stimulation by the protein kinase A (PKA) during increased sympathetic tone. Impaired PKA-mediated stimulation of IKs channels may considerably aggravate dysfunction of the channels induced by mutations in the KCNQ1 gene that encodes the structure of the α-subunit of IKs channels. These mutations are associated with several subtypes of inherited arrhythmias, mainly long QT syndrome type 1, less commonly short QT syndrome type 2, and atrial fibrillation. The impaired PKA reactivity of IKs channels may significantly increase the risk of arrhythmia in these patients. Unfortunately, only approximately 2.7% of the KCNQ1 variants identified as putatively clinically significant have been studied with respect to this problem. This review summarizes the current knowledge in the field to stress the importance of the PKA-mediated regulation of IKs channels, and to appeal for further analysis of this regulation in KCNQ1 mutations associated with inherited arrhythmogenic syndromes. On the basis of the facts summarized in our review, we suggest several new regions of the α-subunit of the IKs channels as potential contributors to PKA stimulation, namely the S4 and S5 segments, and the S2-S3 and S4-S5 linkers. Deeper knowledge of mechanisms of the impaired PKA response in mutated IKs channels may help to better understand this regulation, and may improve risk stratification and management of patients suffering from related pathologies.
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A Physiologic Approach to the Pharmacogenomics of Hypertension.
Eadon, MT, Chapman, AB
Advances in chronic kidney disease. 2016;(2):91-105
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Abstract
Hypertension is a multifactorial condition with diverse physiological systems contributing to its pathogenesis. Individuals exhibit significant variation in their response to antihypertensive agents. Traditional markers, such as age, gender, diet, plasma renin level, and ethnicity, aid in drug selection. However, this review explores the contribution of genetics to facilitate antihypertensive agent selection and predict treatment efficacy. The findings, reproducibility, and limitations of published studies are examined, with emphasis placed on candidate genetic variants affecting drug metabolism, the renin-angiotensin system, adrenergic signalling, and renal sodium reabsorption. Single-nucleotide polymorphisms identified and replicated in unbiased genome-wide association studies of hypertension treatment are reviewed to illustrate the evolving understanding of the disease's complex and polygenic pathophysiology. Implementation efforts at academic centers seek to overcome barriers to the broad adoption of pharmacogenomics in the treatment of hypertension. The level of evidence required to support the implementation of pharmacogenomics in clinical practice is considered.
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β-Adrenergic regulation of the cardiac Na+-K+ ATPase mediated by oxidative signaling.
Galougahi, KK, Liu, CC, Bundgaard, H, Rasmussen, HH
Trends in cardiovascular medicine. 2012;(4):83-7
Abstract
Activation of β-adrenergic receptors (ARs) elicits responses arising from protein kinase A (PKA)-mediated phosphorylation of target proteins that regulate Ca(2+)-dependent excitation-contraction coupling. Some important targets for β-AR- and PKA-dependent pathways, including the sarcolemmal Na(+)-K(+) pump, also undergo oxidative modifications in response to activation of receptor-coupled redox signaling pathways in cardiac myocytes. Here, we highlight how β(1)- and β(3)-AR signaling have opposing effects on functionally important oxidative modification of the Na(+)-K(+) pump molecular complex and how the addition of redox dependence to the canonical phosphorylation dependence of the scheme for β-AR signaling in general expands its versatility but also its complexity. The expanded scheme integrates increased oxidative stress into the pathophysiological effects of adrenergic hyperactivity and provides mechanistic explanation for the efficacy of β-AR blockers in heart failure in which raised intracellular Na(+) levels are detrimental-an explanation not provided by traditionally held views on β-AR-mediated regulation of the pump function.
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Apoptosis in heart failure. -The role of the β-adrenergic receptor-mediated signaling pathway and p53-mediated signaling pathway in the apoptosis of cardiomyocytes-.
Fujita, T, Ishikawa, Y
Circulation journal : official journal of the Japanese Circulation Society. 2011;(8):1811-8
Abstract
The heart works as a driving force to deliver oxygen and nutrients to the whole body. Interrupting this function for only several minutes can cause critical and permanent damage to the human body. Thus, heart failure (HF) or attenuated cardiac function is an important factor that affects both patient's the quality of life and longevity. Numerous clinical and basic studies have been performed to clarify the complex pathophysiology of HF and to develop effective therapies. Modulating the β-adrenergic receptor-mediated signaling pathway has been one of the most crucial targets for HF therapy. Impressively, recent reports identified p53, a well-known tumor suppressor, as a major player in the development of HF. The present review highlights the apoptosis of cardiomyocytes, which is one of the important mechanisms that leads to HF and can be induced by both β-adrenergic signaling and p53. Consideration of the cross-talk among these major pathways will be important when developing effective and safe therapies for HF.
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Structure-function of alpha1-adrenergic receptors.
Perez, DM
Biochemical pharmacology. 2007;(8):1051-62
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Abstract
The Easson-Stedman hypothesis provided the rationale for the first studies of drug design for the alpha(1)-adrenergic receptor. Through chemical modifications of the catecholamine core structure, the need was established for a protonated amine, a beta-hydroxyl on a chiral center, and an aromatic ring with substitutions capable of hydrogen bonding. After the receptors were cloned and three alpha(1)-adrenergic receptor subtypes were discovered, drug design became focused on the analysis of receptor structure and new interactions were uncovered. It became clear that alpha(1)- and beta-adrenergic receptors did not share stringent homology in the ligand-binding pocket but this difference has allowed for more selective drug design. Novel discoveries on allosterism and agonist trafficking may be used in the future design of therapeutics with fewer side effects. This review will explore past and current knowledge of the structure-function of the alpha(1)-adrenergic receptor subtypes.
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Adrenergic regulation of the rapid component of the cardiac delayed rectifier potassium current, I(Kr), and the underlying hERG ion channel.
Thomas, D, Kiehn, J, Katus, HA, Karle, CA
Basic research in cardiology. 2004;(4):279-87
Abstract
Ventricular arrhythmias are often precipitated by physical or emotional stress, in particular in patients with ischemic heart disease or hereditary long QT syndrome. Stimulation of the sympathetic nervous system in response to exercise or emotional stress causes activation of cardiac alpha- and beta-adrenoceptors. The rapid component of the delayed rectifier potassium current, I(Kr), and the underlying hERG potassium channel are critical for the regulation of heart rhythm. Recent experimental studies revealed that hERG/I(Kr) currents are modulated by alpha- and beta-adrenergic stimulation, providing a pathophysiological explanation for the increased incidence of arrhythmias during stress. This review summarizes the current knowledge on hERG/I(Kr) channel modulation by adrenergic activity. In addition, therapeutic approaches to future effective, more genotype-specific antiarrhythmic therapies are discussed.
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The pharmacogenetics of beta2-adrenergic receptors: relevance to asthma.
Liggett, SB
The Journal of allergy and clinical immunology. 2000;(2 Pt 2):S487-92
Abstract
The beta(2)-adrenergic receptor (beta(2)AR) is the molecular target for beta-agonists used in the treatment of asthma. In the human population, 4 polymorphisms of the beta(2)AR coding block have been found, 3 of which result in receptors that have different properties compared with wild-type. To date, clinical studies suggest that these beta(2)AR polymorphisms may alter asthmatic phenotype and the response to beta-agonist therapy, making these variants the first of undoubtedly several genetic loci that will ultimately be found that will provide for individualized therapy in asthma.