Polymorphic Variants of Adrenoceptors: Pharmacology, Physiology, and Role in Disease

Ahles, Andrea; Engelhardt, Stefan

doi:10.1124/pr.113.008219

Cited by 98 publications

(87 citation statements)

References 351 publications

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“…The less common Gly-49 variant exhibits a higher degree of desensitization and more profound agonist-promoted down-regulation compared with the Ser-49 variant when expressed in cell lines (29,58). Furthermore, several clinical associations have been suggested for the polymorphism, although the results have been inconsistent (59). The S49G replacement clearly eliminates the O-glycosite at this position, but it remains to be determined to what degree this amino acid replacement affects glycosylation of other sites in the region and ultimately proteolytic processing.…”

Section: Galnac-t2 Fine-tunes ␤ 1 Ar Ectodomain Cleavagementioning

confidence: 99%

Site-specific O-Glycosylation by Polypeptide N-Acetylgalactosaminyltransferase 2 (GalNAc-transferase T2) Co-regulates β1-Adrenergic Receptor N-terminal Cleavage

Goth

Tuhkanen

Khan

et al. 2017

Journal of Biological Chemistry

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Edited by F. Anne StephensonThe ␤ 1 -adrenergic receptor (␤ 1 AR) is a G protein-coupled receptor (GPCR) and the predominant adrenergic receptor subtype in the heart, where it mediates cardiac contractility and the force of contraction. Although it is the most important target for ␤-adrenergic antagonists, such as ␤-blockers, relatively little is yet known about its regulation. We have shown previously that ␤ 1 AR undergoes constitutive and regulated N-terminal cleavage participating in receptor down-regulation and, moreover, that the receptor is modified by O-glycosylation. Here we demonstrate that the polypeptide GalNAc-transferase 2 (GalNAc-T2) specifically O-glycosylates ␤ 1 AR at five residues in the extracellular N terminus, including the Ser-49 residue at the location of the common S49G single-nucleotide polymorphism. Using in vitro O-glycosylation and proteolytic cleavage assays, a cell line deficient in O-glycosylation, GalNAc-T-edited cell line model systems, and a GalNAc-T2 knock-out rat model, we show that GalNAc-T2 co-regulates the metalloproteinase-mediated limited proteolysis of ␤ 1 AR. Furthermore, we demonstrate that impaired O-glycosylation and enhanced proteolysis lead to attenuated receptor signaling, because the maximal response elicited by the ␤AR agonist isoproterenol and its potency in a cAMP accumulation assay were decreased in HEK293 cells lacking GalNAc-T2. Our findings reveal, for the first time, a GPCR as a target for co-regulatory functions of site-specific O-glycosylation mediated by a unique GalNAc-T isoform. The results provide a new level of ␤ 1 AR regulation that may open up possibilities for new therapeutic strategies for cardiovascular diseases. ␤-Adrenergic receptors (␤ARs)4 are G protein-coupled receptors (GPCRs) that activate intracellular signaling pathways mainly via the stimulatory G s protein after binding of agonists such as adrenaline and noradrenaline (1, 2). The ␤ARs exist as three subtypes, ␤ 1 , ␤ 2 , and ␤ 3 , and the former two are important in the regulation of the excitation-contraction coupling of the myocardium. The ␤ 1 AR is the predominant ␤AR subtype expressed in the heart and the main mediator of the endogenous catecholamine-stimulated positive chronotropy and inotropy (1, 2). Thus, it is the most important target receptor for ␤-adrenergic antagonists, also called ␤-blockers, which are widely used in the treatment of cardiac diseases, such as chronic heart failure, coronary artery disease, arrhythmias, and hypertension. However, these therapeutic agents have limited effectiveness in some patients and also exert adverse effects. Consequently, there is a growing need to better understand the underlying mechanisms in cardiac function and disease to develop alternative and more individualized treatment options that can improve clinical outcomes.During chronic heart failure, a persistent compensatory increase of catecholamines causes ␤ 1 AR desensitization and down-regulation. The density of ␤ 1 ARs at the plasma membrane is reduced by 50%, whereas that of ␤...

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Section: Galnac-t2 Fine-tunes ␤ 1 Ar Ectodomain Cleavagementioning

confidence: 99%

Site-specific O-Glycosylation by Polypeptide N-Acetylgalactosaminyltransferase 2 (GalNAc-transferase T2) Co-regulates β1-Adrenergic Receptor N-terminal Cleavage

Goth

Tuhkanen

Khan

et al. 2017

Journal of Biological Chemistry

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“…The efficacy of ADRB1 signaling and the response to ␤-blockers has been reported to vary among patients, and this has been attributed to sequence variation within the coding sequence of ADRB1 (3). Multiple association studies have identified c.1165CϾG as the most relevant among the variants in ADRB1 (4). This variant is the most common non-synonymous variation in the ADRB1 gene and results in an amino acid substitution from arginine to glycine at position 389 in the ADRB1 protein.…”

mentioning

confidence: 99%

Interhelical Interaction and Receptor Phosphorylation Regulate the Activation Kinetics of Different Human β1-Adrenoceptor Variants

Ahles

Rodewald

Rochais

et al. 2015

Journal of Biological Chemistry

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Background:The mechanism underlying the hyperfunctionality of the Arg-389 variant of the human ␤ 1 -adrenoceptor is elusive. Results: Real-time FRET imaging of the Arg-389 variant in combination with site-directed mutagenesis revealed faster activation kinetics compared with the hypofunctional Gly-389 variant. Conclusion: Interhelical interaction of Arg-389 regulates receptor activation speed and efficacy. Significance: Our findings deepen the understanding of heterogeneity of drug responses observed for the ␤ 1 -adrenoceptor.

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“…Increased allele frequencies of some single nucleotide polymorphisms in the adrenoceptor genes were found in hypertensive patients (Arg492Cys, Asn251Lys, Gly389Arg, Arg16Gly, Gln27Glu, and Arg389). 10 Currently, approximately 4000 variants in the genes encoding adrenoceptors have been identified. 10 However, there is no consensus regarding the impact of the adrenoceptor variants on BP, as well as the therapeutic response and risk for hypertension.…”

mentioning

confidence: 99%

“…10 Currently, approximately 4000 variants in the genes encoding adrenoceptors have been identified. 10 However, there is no consensus regarding the impact of the adrenoceptor variants on BP, as well as the therapeutic response and risk for hypertension. 10 It is well established that RHTN implies on patients with an extreme phenotype, 11 although the prediction that genetic factors play a greater role in these patients than in the general hypertensive population is debatable.…”

mentioning

confidence: 99%

“…10 However, there is no consensus regarding the impact of the adrenoceptor variants on BP, as well as the therapeutic response and risk for hypertension. 10 It is well established that RHTN implies on patients with an extreme phenotype, 11 although the prediction that genetic factors play a greater role in these patients than in the general hypertensive population is debatable. In addition, some studies have already shown the influence of polymorphisms on BP control (WNK1 AluYb8 insertion), 12 cardiovascular risk (I180V), 13 and therapy resistance 14 in RHTN patients.…”

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confidence: 99%

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Does Renal Denervation Fit All Resistant Hypertension? The Role of Genetics

Ritter

Faria

Fontana

et al. 2015

J of Clinical Hypertension

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To the editor Resistant hypertension (RHTN) is a clinical condition associated with high cardiovascular risk and incidence of target organ damage (TOD).1 These patients require intensive pharmacologic and nonpharmacologic approaches to achieve blood pressure (BP) control and prevent TOD progression.2 Despite the great number of drugs available in the clinical setting, the proportion of patients achieving adequate BP levels remains low. 3 Recently, renal denervation (RDN) has emerged as an alternative invasive therapy for these difficult-to-treat patients. The Symplicity HTN-1 and -2 trials, which evaluated the effects of RDN on BP levels in patients with RHTN, 4,5 revealed large BP reductions; however, several methodological concerns of these studies were highlighted.6

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Polymorphic Variants of Adrenoceptors: Pharmacology, Physiology, and Role in Disease

Cited by 98 publications

References 351 publications

Site-specific O-Glycosylation by Polypeptide N-Acetylgalactosaminyltransferase 2 (GalNAc-transferase T2) Co-regulates β1-Adrenergic Receptor N-terminal Cleavage

Site-specific O-Glycosylation by Polypeptide N-Acetylgalactosaminyltransferase 2 (GalNAc-transferase T2) Co-regulates β1-Adrenergic Receptor N-terminal Cleavage

Interhelical Interaction and Receptor Phosphorylation Regulate the Activation Kinetics of Different Human β1-Adrenoceptor Variants

Does Renal Denervation Fit All Resistant Hypertension? The Role of Genetics

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