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Nature Nov 2022G-protein-coupled receptors (GPCRs), the largest family of signalling receptors, as well as important drug targets, are known to activate extracellular-signal-regulated...
G-protein-coupled receptors (GPCRs), the largest family of signalling receptors, as well as important drug targets, are known to activate extracellular-signal-regulated kinase (ERK)-a master regulator of cell proliferation and survival. However, the precise mechanisms that underlie GPCR-mediated ERK activation are not clearly understood. Here we investigated how spatially organized β-adrenergic receptor (βAR) signalling controls ERK. Using subcellularly targeted ERK activity biosensors, we show that βAR signalling induces ERK activity at endosomes, but not at the plasma membrane. This pool of ERK activity depends on active, endosome-localized Gα and requires ligand-stimulated βAR endocytosis. We further identify an endosomally localized non-canonical signalling axis comprising Gα, RAF and mitogen-activated protein kinase kinase, resulting in endosomal ERK activity that propagates into the nucleus. Selective inhibition of endosomal βAR and Gα signalling blunted nuclear ERK activity, MYC gene expression and cell proliferation. These results reveal a non-canonical mechanism for the spatial regulation of ERK through GPCR signalling and identify a functionally important endosomal signalling axis.
Topics: Adrenergic Agents; Cell Proliferation; Endosomes; Extracellular Signal-Regulated MAP Kinases; Genes, myc; GTP-Binding Protein alpha Subunits, Gs; Mitogen-Activated Protein Kinase Kinases; Phosphorylation; Receptors, Adrenergic, beta-2; Signal Transduction
PubMed: 36289326
DOI: 10.1038/s41586-022-05343-3 -
Journal of Clinical Sleep Medicine :... Apr 2020Su P-L, Lin C-Y, Lin S-H. Author response. . 2020;16(4):645–646.
Su P-L, Lin C-Y, Lin S-H. Author response. . 2020;16(4):645–646.
Topics: Adrenergic Agents; Cohort Studies; Humans; Publishing; Research Design; Sleep Apnea Syndromes
PubMed: 32022676
DOI: 10.5664/jcsm.8298 -
Cells Mar 2022Over the last few years, the number of research publications about the role of catecholamines (epinephrine, norepinephrine, and dopamine) in the development of liver... (Review)
Review
Over the last few years, the number of research publications about the role of catecholamines (epinephrine, norepinephrine, and dopamine) in the development of liver diseases such as liver fibrosis, fatty liver diseases, or liver cancers is constantly increasing. However, the mechanisms involved in these effects are not well understood. In this review, we first recapitulate the way the liver is in contact with catecholamines and consider liver implications in their metabolism. A focus on the expression of the adrenergic and dopaminergic receptors by the liver cells is also discussed. Involvement of catecholamines in physiological (glucose metabolism, lipids metabolism, and liver regeneration) and pathophysiological (impact on drug-metabolizing enzymes expression, liver dysfunction during sepsis, fibrosis development, or liver fatty diseases and liver cancers) processes are then discussed. This review highlights the importance of understanding the mechanisms through which catecholamines influence liver functions in order to draw benefit from the adrenergic and dopaminergic antagonists currently marketed. Indeed, as these molecules are well-known drugs, their use as therapies or adjuvant treatments in several liver diseases could be facilitated.
Topics: Adrenergic Agents; Catecholamines; Humans; Liver Neoplasms; Norepinephrine
PubMed: 35326472
DOI: 10.3390/cells11061021 -
Nature Communications Oct 2023Norepinephrine (NE) is a well-known appetite regulator, and the nor/adrenergic system is targeted by several anti-obesity drugs. To better understand the circuitry...
Norepinephrine (NE) is a well-known appetite regulator, and the nor/adrenergic system is targeted by several anti-obesity drugs. To better understand the circuitry underlying adrenergic appetite control, here we investigated the paraventricular hypothalamic nucleus (PVN), a key brain region that integrates energy signals and receives dense nor/adrenergic input, using a mouse model. We found that PVN NE level increases with signals of energy deficit and decreases with food access. This pattern is recapitulated by the innervating catecholaminergic axon terminals originating from NTS-neurons. Optogenetic activation of rostral-NTS → PVN projection elicited strong motivation to eat comparable to overnight fasting whereas its inhibition attenuated both fasting-induced & hypoglycemic feeding. We found that NTS-axons functionally targeted PVN-neurons by predominantly inhibiting them, in part, through α1-AR mediated potentiation of GABA release from ARC presynaptic terminals. Furthermore, glucoprivation suppressed PVN activity, which was required for hypoglycemic feeding response. These results define an ascending nor/adrenergic circuit, NTS → PVN, that conveys peripheral hunger signals to melanocortin pathway.
Topics: Hunger; Melanocortins; Adrenergic Agents; Appetite; Paraventricular Hypothalamic Nucleus; Norepinephrine; Hypoglycemic Agents
PubMed: 37857606
DOI: 10.1038/s41467-023-42362-8 -
Thorax Oct 2019
Topics: Adrenergic Agents; Bronchodilator Agents; Genotype; Humans; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Receptors, Adrenergic, beta-2
PubMed: 31481632
DOI: 10.1136/thoraxjnl-2019-213697 -
Cancer Metastasis Reviews Sep 2022Obesity is an established risk factor for several human cancers. Given the association between excess body weight and cancer, the increasing rates of obesity worldwide... (Review)
Review
Obesity is an established risk factor for several human cancers. Given the association between excess body weight and cancer, the increasing rates of obesity worldwide are worrisome. A variety of obesity-related factors has been implicated in cancer initiation, progression, and response to therapy. These factors include circulating nutritional factors, hormones, and cytokines, causing hyperinsulinemia, inflammation, and adipose tissue dysfunction. The impact of these conditions on cancer development and progression has been the focus of extensive literature. In this review, we concentrate on processes that can link obesity and cancer, and which provide a novel perspective: extracellular matrix remodeling, angiogenesis, and adrenergic signaling. We describe molecular mechanisms involved in these processes, which represent putative targets for intervention. Liver, pancreas, and breast cancers were chosen as exemplary disease models. In view of the expanding epidemic of obesity, a better understanding of the tumorigenic process in obese individuals might lead to more effective treatments and preventive measures.
Topics: Adipose Tissue; Adrenergic Agents; Extracellular Matrix; Humans; Neoplasms; Obesity
PubMed: 36074318
DOI: 10.1007/s10555-022-10058-y -
Nature Communications Jul 2022β-Adrenergic signaling is a core regulator of brown adipocyte function stimulating both lipolysis and transcription of thermogenic genes, thereby expanding the capacity...
β-Adrenergic signaling is a core regulator of brown adipocyte function stimulating both lipolysis and transcription of thermogenic genes, thereby expanding the capacity for oxidative metabolism. We have used pharmacological inhibitors and a direct activator of lipolysis to acutely modulate the activity of lipases, thereby enabling us to uncover lipolysis-dependent signaling pathways downstream of β-adrenergic signaling in cultured brown adipocytes. Here we show that induction of lipolysis leads to acute induction of several gene programs and is required for transcriptional regulation by β-adrenergic signals. Using machine-learning algorithms to infer causal transcription factors, we show that PPARs are key mediators of lipolysis-induced activation of genes involved in lipid metabolism and thermogenesis. Importantly, however, lipolysis also activates the unfolded protein response and regulates the core circadian transcriptional machinery independently of PPARs. Our results demonstrate that lipolysis generates important metabolic signals that exert profound pleiotropic effects on transcription and function of cultured brown adipocytes.
Topics: Adipocytes, Brown; Adipose Tissue, Brown; Adrenergic Agents; Lipolysis; Peroxisome Proliferator-Activated Receptors; Thermogenesis
PubMed: 35803907
DOI: 10.1038/s41467-022-31525-8 -
Archives of Razi Institute Feb 2022The current study was conducted to investigate the interaction between the central adrenergic and histaminergic systems and the broiler chick's feed intake. In the first...
The current study was conducted to investigate the interaction between the central adrenergic and histaminergic systems and the broiler chick's feed intake. In the first experiment, the intracerebroventricular (ICV) injection of solutions was conducted which included 10 nmol of prazosin (an α-receptor antagonist), 300 nmol of histamine, co-injection of prazosin and histamine. Experiments two to five were conducted similarly the same as the first experiment, in which chickens were ICV injected with 13 nmol of yohimbine (an α-receptor antagonist), 24 nmol of metoprolol (a β adrenergic receptor antagonist), 5 nmol of ICI 118,551 (a β adrenergic receptor antagonist), and 20 nmol of SR 59230R (a β adrenergic receptor antagonist). The injected solutions in the sixth experiment included 300 nmol of noradrenaline, 250 nmol of α-FMH (an alpha fluoromethyl histidine), noradrenaline, and α-FMH. Seventh to ninth experiments were similar to the sixth experiment, except that the chickens were ICV injected with 300 nmol of chlorpheniramine (a histamine H receptors antagonist), 82 nmol of famotidine (a histamine H receptors antagonist), and 300 nmol of thioperamide (a histamine H receptors antagonist), rather than α-FMH. Afterward, the cumulative food intake was measured 120 min after injection. Based on the obtained results, both histamine ICV injection and noradrenaline injection reduced food intake (<0.05). Moreover, co-injection of histamine and ICI 118,551 (<0.05), and co-injection of noradrenaline and Chlorpheniramine reduced food intake (<0.05). In addition, noradrenaline and Thioperamide co-injection improved hypophagic effect of noradrenaline in neonatal chicken (<0.05). These findings suggested the effect of interconnection between adrenergic and histaminergic systems, which may be mediated by H and H histaminergic and β adrenergic receptors, on the regulation of food intake in the neonatal broiler chicken.
Topics: Adrenergic Agents; Adrenergic Antagonists; Animals; Animals, Newborn; Appetite; Chickens; Chlorpheniramine; Feeding Behavior; Histamine; Norepinephrine; Prazosin; Receptors, Adrenergic; Receptors, Histamine
PubMed: 35891757
DOI: 10.22092/ARI.2021.354450.1638 -
Journal of Neuroinflammation Nov 2023Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common...
BACKGROUND
Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of POI development. However, the glia-restricted responses and activation mechanisms are poorly understood. The sympathetic nervous system becomes rapidly activated by abdominal surgery. It modulates intestinal immunity, innervates all intestinal layers, and directly interfaces with enteric glia. We hypothesized that sympathetic innervation controls enteric glia reactivity in response to surgical trauma.
METHODS
Sox10/Rpl22 mice were subjected to a mouse model of laparotomy or intestinal manipulation to induce POI. Histological, protein, and transcriptomic analyses were performed to analyze glia-specific responses. Interactions between the sympathetic nervous system and enteric glia were studied in mice chemically depleted of TH sympathetic neurons and glial-restricted Sox10/JellyOP/Rpl22 mice, allowing optogenetic stimulation of β-adrenergic downstream signaling and glial-specific transcriptome analyses. A laparotomy model was used to study the effect of sympathetic signaling on enteric glia in the absence of intestinal manipulation. Mechanistic studies included adrenergic receptor expression profiling in vivo and in vitro and adrenergic agonism treatments of primary enteric glial cell cultures to elucidate the role of sympathetic signaling in acute enteric gliosis and POI.
RESULTS
With ~ 4000 differentially expressed genes, the most substantial enteric glia response occurs early after intestinal manipulation. During POI, enteric glia switch into a reactive state and continuously shape their microenvironment by releasing inflammatory and migratory factors. Sympathetic denervation reduced the inflammatory response of enteric glia in the early postoperative phase. Optogenetic and pharmacological stimulation of β-adrenergic downstream signaling triggered enteric glial reactivity. Finally, distinct adrenergic agonists revealed β-1/2 adrenoceptors as the molecular targets of sympathetic-driven enteric glial reactivity.
CONCLUSIONS
Enteric glia act as early responders during post-traumatic intestinal injury and inflammation. Intact sympathetic innervation and active β-adrenergic receptor signaling in enteric glia is a trigger of the immediate glial postoperative inflammatory response. With immune-activating cues originating from the sympathetic nervous system as early as the initial surgical incision, adrenergic signaling in enteric glia presents a promising target for preventing POI development.
Topics: Animals; Mice; Gliosis; Adrenergic Agents; Neuroglia; Signal Transduction; Sympathetic Nervous System; Enteric Nervous System
PubMed: 37941007
DOI: 10.1186/s12974-023-02937-0 -
BMC Geriatrics Sep 2022Adrenergic alpha-1 receptor antagonists (alpha-1 antagonists) are frequently used medications in the management of lower urinary tract symptoms (LUTS) suggestive of... (Meta-Analysis)
Meta-Analysis
Efficacy and safety of adrenergic alpha-1 receptor antagonists in older adults: a systematic review and meta-analysis supporting the development of recommendations to reduce potentially inappropriate prescribing.
BACKGROUND
Adrenergic alpha-1 receptor antagonists (alpha-1 antagonists) are frequently used medications in the management of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and in the management of therapy-resistant arterial hypertension, two conditions frequently found in older adults. This systematic review aims at presenting a complete overview of evidence over the benefits and risks of alpha-1 antagonist treatment in people ≥ 65 years, and at deriving recommendations for a safe application of alpha-1 antagonists in older adults from the evidence found.
METHODS
A comprehensive literature search was performed (last update March 25 2022) including multiple databases (Medline/Pubmed, Embase, the Cochrane Library) and using the PICOS framework to define search terms. The selection of the studies was done by two independent reviewers in a two-step approach, followed by a systematic data extraction. Quality appraisal was performed for each study included using standardised appraisal tools. The studies retrieved and additional literature were used for the development of recommendations, which were rated for strength and quality according to the GRADE methodology.
RESULTS
Eighteen studies were included: 3 meta-analyses, 6 randomised controlled trials and 9 observational trials. Doxazosin in the management of arterial hypertension was associated with a higher risk of cardiovascular disease, particularly heart failure, than chlorthalidone. Regarding treatment of LUTS suggestive of BPH, alpha-1 antagonists appeared to be effective in the relief of urinary symptoms and improvement of quality of life. They seemed to be less effective in preventing disease progression. Analyses of the risk profile indicated an increase in vasodilation related adverse events and sexual adverse events for some agents. The risk of falls and fractures as well as the effects of long-term treatment remained unclear. All meta-analyses and 5 out of 6 interventional studies were downgraded in the quality appraisal. 7 out of 9 observational studies were of good quality.
CONCLUSIONS
It cannot be recommended to use doxazosin as first-line antihypertensive agent neither in older adults nor in younger patients. In the management of BPH alpha-1 antagonists promise to effectively relieve urinary symptoms with uncertainty regarding their efficacy in preventing long-term progression events.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Aged; Antihypertensive Agents; Chlorthalidone; Doxazosin; Humans; Hypertension; Inappropriate Prescribing; Lower Urinary Tract Symptoms; Male; Prostatic Hyperplasia; Quality of Life
PubMed: 36171560
DOI: 10.1186/s12877-022-03415-7