-
Frontiers in Immunology 2023Anti-CD40 agonistic antibody (αCD40), an activator of dendritic cells (DC) can enhance antigen presentation and activate cytotoxic T-cells against poorly immunogenic...
INRODUCTION
Anti-CD40 agonistic antibody (αCD40), an activator of dendritic cells (DC) can enhance antigen presentation and activate cytotoxic T-cells against poorly immunogenic tumors. However, cancer immunotherapy trials also suggest that αCD40 is only moderately effective in patients, falling short of achieving clinical success. Identifying factors that decrease αCD40 immune-stimulating effects can aid the translation of this agent to clinical reality.
METHOD/RESULTS
Here, we reveal that β-adrenergic signaling on DCs directly interferes with αCD40 efficacy in immunologically cold head and neck tumor model. We discovered that β-2 adrenergic receptor (β2AR) activation rewires CD40 signaling in DCs by directly inhibiting the phosphorylation of IκBα and indirectly by upregulating levels of phosphorylated-cAMP response element-binding protein (pCREB). Importantly, the addition of propranolol, a pan β-Blocker reprograms the CD40 pathways, inducing superior tumor regressions, increased infiltration of cytotoxic T-cells, and a reduced burden of regulatory T-cells in tumors compared to monotherapy.
DISCUSSION/CONCLUSION
Thus, our study highlights an important mechanistic link between stress-induced β2AR signaling and reduced αCD40 efficacy in cold tumors, providing a new combinatorial approach to improve clinical outcomes in patients.
Topics: Humans; Dendritic Cells; CD40 Antigens; T-Lymphocytes, Cytotoxic; Neoplasms; Receptors, Adrenergic
PubMed: 37006295
DOI: 10.3389/fimmu.2023.1141712 -
Cells Apr 2019The beta-3 adrenergic receptor (β-AR) is by far the least studied isotype of the beta-adrenergic sub-family. Despite its study being long hampered by the lack of... (Review)
Review
The beta-3 adrenergic receptor (β-AR) is by far the least studied isotype of the beta-adrenergic sub-family. Despite its study being long hampered by the lack of suitable animal and cellular models and inter-species differences, a substantial body of literature on the subject has built up in the last three decades and the physiology of β-AR is unraveling quickly. As will become evident in this work, β-AR is emerging as an appealing target for novel pharmacological approaches in several clinical areas involving metabolic, cardiovascular, urinary, and ocular disease. In this review, we will discuss the most recent advances regarding β-AR signaling and function and summarize how these findings translate, or may do so, into current clinical practice highlighting β-AR's great potential as a novel therapeutic target in a wide range of human conditions.
Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-3 Receptor Antagonists; Animals; Epinephrine; Humans; Norepinephrine; Receptors, Adrenergic, beta-3; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 30995798
DOI: 10.3390/cells8040357 -
Journal of Receptor and Signal... Apr 2011Sympathetic nervous system regulation by the α(1)-adrenergic receptor (AR) subtypes (α(1A), α(1B), α(1D)) is complex, whereby chronic activity can be either... (Review)
Review
Sympathetic nervous system regulation by the α(1)-adrenergic receptor (AR) subtypes (α(1A), α(1B), α(1D)) is complex, whereby chronic activity can be either detrimental or protective for both heart and brain function. This review will summarize the evidence that this dual regulation can be mediated through the different α(1)-AR subtypes in the context of cardiac hypertrophy, heart failure, apoptosis, ischemic preconditioning, neurogenesis, locomotion, neurodegeneration, cognition, neuroplasticity, depression, anxiety, epilepsy, and mental illness.
Topics: Animals; Cytoprotection; Humans; Myocardium; Neurons; Protective Agents; Receptors, Adrenergic, alpha-1
PubMed: 21338248
DOI: 10.3109/10799893.2010.550008 -
Cellular Signalling Feb 2021β1-adrenergic receptor (β1AR)-mediated transactivation of epidermal growth factor receptor (EGFR) engages downstream signaling events that impact numerous cellular...
β1-adrenergic receptor (β1AR)-mediated transactivation of epidermal growth factor receptor (EGFR) engages downstream signaling events that impact numerous cellular processes including growth and survival. While association of these receptors has been shown to occur basally and be important for relaying transactivation-specific intracellular events, the mechanism by which they do so is unclear and elucidation of which would aid in understanding the consequence of disrupting their interaction. Using fluorescence resonance energy transfer (FRET) and immunoprecipitation (IP) analyses, we evaluated the impact of C-terminal truncations of EGFR on its ability to associate with β1AR. While loss of the last 230 amino acid C-terminal phosphotyrosine-rich domain did not disrupt the ability of EGFR to associate with β1AR, truncation of the entire intracellular domain of EGFR resulted in almost complete loss of its interaction with β1AR, suggesting that either the kinase domain or juxtamembrane domain (JMD) may be required for this association. Treatment with the EGFR antagonist gefitinib did not prevent β1AR-EGFR association, however, treatment with a palmitoylated peptide encoding the first 20 amino acids of the JMD domain (JMD-A) disrupted β1AR-EGFR association over time and prevented β1AR-mediated ERK1/2 phosphorylation, both in general and specifically in association with EGFR. Conversely, neither a mutated JMD-A peptide nor a palmitoylated peptide fragment consisting of the subsequent 18 amino acids of the JMD domain (JMD-B) were capable of doing so. Altogether, the proximal region of the JMD of EGFR is responsible for its association with β1AR, and its disruption prevents β1AR-mediated transactivation, thus providing a new tool to study the functional consequences of disrupting β1AR-EGFR downstream signaling.
Topics: Cell Line, Tumor; ErbB Receptors; Humans; Peptides; Protein Domains; Receptors, Adrenergic, beta-1; Signal Transduction
PubMed: 33238186
DOI: 10.1016/j.cellsig.2020.109846 -
Medicina (Kaunas, Lithuania) 2004Beta-adrenergic receptors have been subdivided into three types: beta1-, beta2- and beta3-adrenergic receptors. beta1-adrenergic receptors are predominant in the heart,... (Comparative Study)
Comparative Study Review
Beta-adrenergic receptors have been subdivided into three types: beta1-, beta2- and beta3-adrenergic receptors. beta1-adrenergic receptors are predominant in the heart, beta2-adrenergic receptors--in the respiratory system, and beta3-adrenergic receptors--in the adipose tissues. However, since 1989, when beta3-adrenergic receptor was cloned, numerous biochemical and functional studies have confirmed its presence in various species and tissues, including the heart. Unlike beta1- and beta2-adrenergic receptors, it has been shown that beta3-adrenergic receptors possess the cardiodepressant effects in human ventricles, what did not fit to its stimulatory properties of adenylyl cyclase in other tissues. In this regard, the role of beta3-adrenergic receptors in the regulation of cardiac function may be of great importance in pathological conditions and remains undetermined, so far. In this review brief characterization of beta3-adrenergic receptors, concerning their structure, function and possible pathophysiological role is provided.
Topics: Adenylyl Cyclases; Adrenergic beta-2 Receptor Antagonists; Adrenergic beta-3 Receptor Antagonists; Adrenergic beta-Agonists; Animals; Atrial Function; CHO Cells; Cardiovascular Physiological Phenomena; Cattle; Cricetinae; Cricetulus; Enzyme Activation; Haplorhini; Heart; Heart Atria; Heart Failure; Heart Ventricles; Humans; Ligands; Mice; Mice, Knockout; Myocardial Contraction; Myocardium; RNA, Messenger; Rats; Receptors, Adrenergic, beta-2; Receptors, Adrenergic, beta-3; Ventricular Function
PubMed: 15170407
DOI: No ID Found -
Cell Reports. Medicine Feb 2023While brown adipose tissue (BAT) is activated by the beta-3-adrenergic receptor (ADRB3) in rodents, in human brown adipocytes, the ADRB2 is dominantly present and... (Randomized Controlled Trial)
Randomized Controlled Trial
While brown adipose tissue (BAT) is activated by the beta-3-adrenergic receptor (ADRB3) in rodents, in human brown adipocytes, the ADRB2 is dominantly present and responsible for noradrenergic activation. Therefore, we performed a randomized double-blinded crossover trial in young lean men to compare the effects of single intravenous bolus of the ADRB2 agonist salbutamol without and with the ADRB1/2 antagonist propranolol on glucose uptake by BAT, assessed by dynamic 2-[F]fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography scan (i.e., primary outcome). Salbutamol, compared with salbutamol with propranolol, increases glucose uptake by BAT, without affecting the glucose uptake by skeletal muscle and white adipose tissue. The salbutamol-induced glucose uptake by BAT positively associates with the increase in energy expenditure. Notably, participants with high salbutamol-induced glucose uptake by BAT have lower body fat mass, waist-hip ratio, and serum LDL-cholesterol concentration. In conclusion, specific ADRB2 agonism activates human BAT, which warrants investigation of ADRB2 activation in long-term studies (EudraCT: 2020-004059-34).
Topics: Male; Humans; Albuterol; Adipose Tissue, Brown; Propranolol; Glucose; Receptors, Adrenergic; Receptors, Adrenergic, beta-3
PubMed: 36812890
DOI: 10.1016/j.xcrm.2023.100942 -
Nature Mar 2023The third intracellular loop (ICL3) of the G protein-coupled receptor (GPCR) fold is important for the signal transduction process downstream of receptor activation....
The third intracellular loop (ICL3) of the G protein-coupled receptor (GPCR) fold is important for the signal transduction process downstream of receptor activation. Despite this, the lack of a defined structure of ICL3, combined with its high sequence divergence among GPCRs, complicates characterization of its involvement in receptor signalling. Previous studies focusing on the β adrenergic receptor (βAR) suggest that ICL3 is involved in the structural process of receptor activation and signalling. Here we derive mechanistic insights into the role of ICL3 in βAR signalling, observing that ICL3 autoregulates receptor activity through a dynamic conformational equilibrium between states that block or expose the receptor's G protein-binding site. We demonstrate the importance of this equilibrium for receptor pharmacology, showing that G protein-mimetic effectors bias the exposed states of ICL3 to allosterically activate the receptor. Our findings additionally reveal that ICL3 tunes signalling specificity by inhibiting receptor coupling to G protein subtypes that weakly couple to the receptor. Despite the sequence diversity of ICL3, we demonstrate that this negative G protein-selection mechanism through ICL3 extends to GPCRs across the superfamily, expanding the range of known mechanisms by which receptors mediate G protein subtype selective signalling. Furthermore, our collective findings suggest ICL3 as an allosteric site for receptor- and signalling pathway-specific ligands.
Topics: Receptors, Adrenergic, beta-2; Signal Transduction; Heterotrimeric GTP-Binding Proteins; Ligands; Allosteric Site; Protein Conformation
PubMed: 36890236
DOI: 10.1038/s41586-023-05789-z -
Gaceta Medica de Mexico 2018Adrenaline and noradrenaline bind to membrane receptors of the superfamily of G protein-coupled receptors (GPCR) in target cells, where they modulate physiological... (Review)
Review
Adrenaline and noradrenaline bind to membrane receptors of the superfamily of G protein-coupled receptors (GPCR) in target cells, where they modulate physiological responses such as metabolism, vasoconstriction, vasodilation and proliferation. Alteration in their function is associated with conditions such as hypertension, benign prostatic hyperplasia and cardiac hypertrophy. In response to adrenaline, receptors form signaling complexes, which enables adrenergic action to be specific, rapid and efficient. These signaling complexes or signalosomes are composed of kinases, phosphatases, and adapter and scaffold proteins, which together modulate the receptor function. Manipulation of each protein-protein interaction of the adrenergic signaling complex emerges as a promising therapeutic strategy for the design of drugs that modulate adrenergic action and help to define its pathophysiological significance. An important biological model to perform these investigations is the heart, since it expresses all adrenergic receptors; to date, several heart signalosomes have been described. Mass spectrometry (proteomics), genetic manipulation and biochemical assays, such as two-hybrid and co-immunoprecipitation assays, are tools that are used in these studies.
Topics: Epinephrine; Humans; Norepinephrine; Receptors, Adrenergic; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 29733063
DOI: 10.24875/GMM.18002390 -
Endocrinology and Metabolism (Seoul,... Apr 2022Obesity, the prevalence of which is increasing due to the lack of exercise and increased consumption of Westernized diets, induces various complications, including...
BACKGROUND
Obesity, the prevalence of which is increasing due to the lack of exercise and increased consumption of Westernized diets, induces various complications, including ophthalmic diseases. For example, obesity is involved in the onset of cataracts.
METHODS
To clarify the effects and mechanisms of midodrine, an α1-adrenergic receptor agonist, in cataracts induced by obesity, we conducted various analytic experiments in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a rat model of obesity.
RESULTS
Midodrine prevented cataract occurrence and improved lens clearance in OLETF rats. In the lenses of OLETF rats treated with midodrine, we observed lower levels of aldose reductase, tumor necrosis factor-α, and sorbitol, but higher levels of hexokinase, 5'-adenosine monophosphate-activated protein kinase-alpha, adenosine 5´-triphosphate, peroxisome proliferator-activated receptordelta, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, superoxide dismutase, and catalase.
CONCLUSION
The ameliorating effects of midodrine on cataracts in the OLETF obesity rat model are exerted via the following three mechanisms: direct inhibition of the biosynthesis of sorbitol, which causes cataracts; reduction of reactive oxygen species and inflammation; and (3) stimulation of normal aerobic glycolysis.
Topics: Animals; Cataract; Glycolysis; Midodrine; Obesity; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Receptors, Adrenergic; Sorbitol
PubMed: 35316888
DOI: 10.3803/EnM.2021.1237 -
Journal of Musculoskeletal & Neuronal... 2008Evidence that leptin regulates bone turnover in part through a central nervous system (CNS)/beta-adrenergic system relay has driven attention towards the potential... (Review)
Review
Evidence that leptin regulates bone turnover in part through a central nervous system (CNS)/beta-adrenergic system relay has driven attention towards the potential therapeutic benefits of beta-adrenergic blockade to improve bone mass and strength. beta2- adrenergic receptor-mediated signaling in osteoblasts inhibits bone formation and triggers RANKL-mediated osteoclastogenesis and bone resorption. Mouse models of adrenergic-deficiency, particularly the mouse lacking the beta2-adrenergic receptor, have increased bone mass, more specifically increased trabecular bone volume. In turn, beta-blockers, such as propranolol, were reported to inhibit ovariectomy-induced bone loss. In contrast, a number of experiments in mice and rats suggest that inhibition of beta-adrenergic receptor-mediated signaling does not improve, and could actually be detrimental, for bone mass and microstructure. In humans, epidemiological observations suggested that users of beta-blockers have higher bone mineral density (BMD) and/or a reduced risk of fractures, yet not all studies were concordant. Here we review the evidence for a role of the adrenergic system in the regulation of bone metabolism in vitro and in vivo and provide some new evidence for a dual role of beta-adrenergic receptors 1 and 2 on bone turnover. Furthermore, we will examine the similarities and disparities that may exist in the effects of beta-adrenergic and PTH stimulation on bone metabolism.
Topics: Adrenergic Agents; Adrenergic Agonists; Adrenergic Antagonists; Animals; Bone Remodeling; Bone Resorption; Bone and Bones; Humans; Osteoclasts; Osteoporosis; Parathyroid Hormone; Receptors, Adrenergic; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Signal Transduction
PubMed: 18622078
DOI: No ID Found