The Expanding Spectrum of G Protein Diseases

Farfel, Zvi; Bourne, Henry R.; Iiri, Taroh

doi:10.1056/nejm199904013401306

Cited by 268 publications

(175 citation statements)

References 50 publications

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“…Agonist binding to the βARs triggers changes in stimulatory guanine nucleotide-binding proteins, which activate adenylyl cyclases, leading to increased intracellular cyclic adenosine monophosphate (cAMP) levels, and thereby, to increased PKA activity (Farfel et al 1999). PKA phosphorylates proteins in the heart which alter intracellular calcium handling and the calcium sensitivity of myofilaments (reviewed in Sharma and McNeill 2011).…”

Section: Resultsmentioning

confidence: 99%

“…Activation of these receptor subtypes in cardiomyocytes increases cardiac contractile force and contraction rate, increases conduction velocity and automaticity, and increases blood pressure (reviewed in Ho et al 2010;Taylor and Bristow 2004). 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).…”

Section: Discussionmentioning

confidence: 99%

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

Spindler

Mote

et al. 2013

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Chronic treatment with β-adrenergic receptor (βAR) agonists increases mortality and morbidity while βAR antagonists (β-blockers) decrease allcause mortality for those at risk of cardiac disease. Levels of sympathetic nervous system βAR agonists and βAR activity increase with age, and this increase may hasten the development of age-related mortality.Here, we show that β-blockers extend the life span of healthy metazoans. The β-blockers metoprolol and nebivolol, administered in food daily beginning at 12 months of age, significantly increase the mean and median life span of isocalorically fed, male C3B6F1 mice, by 10 and 6.4 %, respectively (P< 0.05). Neither drug affected the weight or food intake of the mice, indicating that induced CR is not responsible for these effects, and that energy absorption and utilization are not altered by the drugs. Both β-blockers were investigated to control for their idiosyncratic, off-target effects. Metoprolol and nebivolol extended Drosophila life span, without affecting food intake or locomotion. Thus, βAR antagonists are capable of directly extending the life span of two widely divergent metazoans, suggesting that these effects are phylogenetically highly conserved. Thus, long-term use of β-blockers, which are generally well-tolerated, may enhance the longevity of healthy humans.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Spindler

Mote

et al. 2013

AGE

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“…1 Their activation is the principal mechanism through which stimulated heptahelical receptors generate changes in intracellular function. 1 Siffert et al 2 identified a common C825T polymorphism in exon 10 of the b 3 -subunit of the heterotrimeric G-protein.…”

Section: Introductionmentioning

confidence: 99%

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

et al. 2003

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The 825T allele of the G-protein b 3 -subunit is associated with increased intracellular signalling. Its association with hypertension is inconsistent. We, therefore, studied the C825T polymorphism in relation to ambulatory blood pressure as well as left ventricular structure and function in two European populations. We genotyped 248 parents and 318 offspring, enrolled in the European Project on Genes in Hypertension in Cracow, Poland (n ¼ 286) and in Novosibirsk, Russian Federation (n ¼ 280). The 24-h ambulatory blood pressure was recorded using oscillometric SpaceLabs 90207 monitors. Within each centre, a single observer performed two-dimensionally guided M-mode echocardiography and Doppler sonography to measure left ventricular structure (American Society of Echocardiography conventions) and diastolic function: early (E) and late (A) peak diastolic inflow velocities. We used analysis of covariance and generalized estimating equations to allow for covariables and nonindependence among related subjects. Genotype frequencies were similar (P ¼ 0.25) in Cracow and Novosibirsk and amounted to 44.7% for CC, 47.2% for CT, and 8.1% for TT. Among parents (mean age: 51.3 years)Fbut not among offspring (mean age 25.1 years)F24-h, daytime and night time systolic blood pressures were 5-6 mmHg higher in TT homozygotes than in C allele carriers. In TT homozygous parents (À8.2 cm/sec, P ¼ 0.004) as well as in TT homozygous offspring (À7.5 cm/sec, P ¼ 0.02), the E-wave was significantly reduced, which in offspring also resulted in a lower E/A ratio (-0.25, P ¼ 0.002). Neither in parents nor in offspring, left ventricular mass index was associated with the C825T polymorphism. In conclusion, in TT homozygotes of both generations, early left ventricular relaxation was reduced. In TT homozygous parents, the latter observation might be because of the higher systolic pressure associated with the TT genotype.

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“…18 Binding of agonist to the receptor leads to a guanine nucleotide binding protein (G s protein) coupled response and conversion of adenosine 5 0 triphosphate to cyclic adenosine 3 0 ,5 0 monophosphate (cAMP) by adenylate cyclase. 5,19 Intracellular rises in cAMP provide an indirect measure of ADRB activity. Increased cAMP stimulates a chain of events that culminates with removal of calcium from contractile protein (faster relaxation in the case of myocytes) and increased activation of contraction through greater calcium cycling; the global effect is improved systolic and diastolic function.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics of the human beta-adrenergic receptors

Taylor

2006

Pharmacogenomics J

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The beta-adrenergic receptors (ADRBs) are cell surface receptors that play central roles in the sympathetic nervous system. Pharmacological targeting of two of these receptors, ADRB1 and ADRB2, represents a widely used therapeutic approach for common and important diseases including asthma, hypertension and heart failure. Genetic variation in both ADRB1 and ADRB2 has been linked to both in vitro and clinical disease phenotypes. More recently, interest has shifted to studies that explore potential interaction between variation in ADRBs and medications directed at these important receptors. This paper reviews the current state of knowledge and understanding of ADRB genetic variation and explores the likely direction of future studies in this area.

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The Expanding Spectrum of G Protein Diseases

Cited by 268 publications

References 50 publications

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

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

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

Pharmacogenetics of the human beta-adrenergic receptors

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