-
Frontiers in Endocrinology 2020Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, characterized by excessive release of catecholamines (CAs), and manifested as the classic triad... (Review)
Review
Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, characterized by excessive release of catecholamines (CAs), and manifested as the classic triad of headaches, palpitations, profuse sweating, and a variety of other signs and symptoms. The diagnosis of PPGL requires both evidence of excessive release of CAs and anatomical localization of CA-secreting tumor. Surgery is the mainstay of treatment for all patients with PPGL unless contraindicated. However, without proper preparation, the release of excessive CAs, especially during surgery, can result in lethal cardiovascular complications. Herein, we briefly reviewed the pathogenesis of this disease, discussed the current approaches and evidence available for preoperative management, summarizing the results of the latest studies which compared the efficacies of preoperative management with or without α adrenergic-receptor antagonists, aiming to facilitate better understanding of the preoperative management of PPGL for the physicians.
Topics: Adrenal Gland Neoplasms; Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Calcium Channel Blockers; Catecholamines; Enzyme Inhibitors; Humans; Hypertension; Pheochromocytoma; Preoperative Care; Receptors, Adrenergic; alpha-Methyltyrosine
PubMed: 33117294
DOI: 10.3389/fendo.2020.586795 -
Annals of Medicine Dec 2022Phytochemicals have garnered much attention because they are useful in managing several human diseases. Yohimbine is one such phytochemical with significant... (Review)
Review
Phytochemicals have garnered much attention because they are useful in managing several human diseases. Yohimbine is one such phytochemical with significant pharmacological potential and could be exploited for research by medicinal chemists. It is an indole alkaloid obtained from various natural/synthetic sources. The research on yohimbine started early, and its use as a stimulant and aphrodisiac by humans has been reported for a long time. The pharmacological activity of yohimbine is mediated by the combined action of the central and peripheral nervous systems. It selectively blocks the pre and postsynaptic α-adrenergic receptors and has a moderate affinity for 1 and 2 subtypes. Yohimbine also binds to other behaviourally relevant monoaminergic receptors in the following order: α-2 NE > 5HT-1A>, 5HT-1B > 1-D > D3 > D2 receptors. The current review highlights some significant findings that contribute to developing yohimbine-based drugs. It also highlights the therapeutic potential of yohimbine against selected human diseases. However, further research is recommended on the pharmacokinetics, molecular mechanisms, and drug safety requirements using well-designed randomized clinical trials to produce yohimbine as a pharmaceutical agent for human use.Key MessagesYohimbine is a natural indole alkaloid with significant pharmacological potential.Humans have used it as a stimulant and aphrodisiac from a relatively early time.It blocks the pre- and postsynaptic α2-adrenergic receptors that could be exploited for managing erectile dysfunction, myocardial dysfunction, inflammatory disorders, and cancer.
Topics: Male; Humans; Yohimbine; Adrenergic alpha-Antagonists; Aphrodisiacs; Receptors, Adrenergic, alpha-2; Pharmaceutical Preparations
PubMed: 36263866
DOI: 10.1080/07853890.2022.2131330 -
Cell Metabolism Aug 2020Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting...
Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the β-adrenergic receptor (β-AR), the adrenergic receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of β-AR. Oral administration of the β-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. This led to off-target binding to β-AR and β-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. ADRB2 was co-expressed with UCP1 in human brown adipocytes. Pharmacological stimulation and inhibition of the β-AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through β-AR signaling in humans (ClinicalTrials.govNCT02811289).
Topics: Adipocytes, Brown; Adolescent; Adult; Animals; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Receptors, Adrenergic, beta-2; Thermogenesis; Young Adult
PubMed: 32755608
DOI: 10.1016/j.cmet.2020.07.005 -
The Journal of Clinical Investigation Jan 2022The dysregulation of energy homeostasis in obesity involves multihormone resistance. Although leptin and insulin resistance have been well characterized, catecholamine...
The dysregulation of energy homeostasis in obesity involves multihormone resistance. Although leptin and insulin resistance have been well characterized, catecholamine resistance remains largely unexplored. Murine β3-adrenergic receptor expression in adipocytes is orders of magnitude higher compared with that of other isoforms. While resistant to classical desensitization pathways, its mRNA (Adrb3) and protein expression are dramatically downregulated after ligand exposure (homologous desensitization). β3-Adrenergic receptor downregulation also occurs after high-fat diet feeding, concurrent with catecholamine resistance and elevated inflammation. This downregulation is recapitulated in vitro by TNF-α treatment (heterologous desensitization). Both homologous and heterologous desensitization of Adrb3 were triggered by induction of the pseudokinase TRIB1 downstream of the EPAC/RAP2A/PI-PLC pathway. TRIB1 in turn degraded the primary transcriptional activator of Adrb3, CEBPα. EPAC/RAP inhibition enhanced catecholamine-stimulated lipolysis and energy expenditure in obese mice. Moreover, adipose tissue expression of genes in this pathway correlated with body weight extremes in a cohort of genetically diverse mice and with BMI in 2 independent cohorts of humans. These data implicate a signaling axis that may explain reduced hormone-stimulated lipolysis in obesity and resistance to therapeutic interventions with β3-adrenergic receptor agonists.
Topics: 3T3-L1 Cells; Adipocytes; Animals; Catecholamines; Down-Regulation; Drug Resistance; Energy Metabolism; Lipolysis; Male; Mice; Obesity; Receptors, Adrenergic, beta-3; Signal Transduction
PubMed: 34847077
DOI: 10.1172/JCI153357 -
Science (New York, N.Y.) Dec 2023Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) bind to extracellular ligands and drugs and modulate intracellular responses...
Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) bind to extracellular ligands and drugs and modulate intracellular responses through conformational changes. Despite their importance as drug targets, the molecular origins of pharmacological properties such as efficacy (maximum signaling response) and potency (the ligand concentration at half-maximal response) remain poorly understood for any ligand-receptor-signaling system. We used the prototypical adrenaline-β2 adrenergic receptor-G protein system to reveal how specific receptor residues decode and translate the information encoded in a ligand to mediate a signaling response. We present a data science framework to integrate pharmacological and structural data to uncover structural changes and allosteric networks relevant for ligand pharmacology. These methods can be tailored to study any ligand-receptor-signaling system, and the principles open possibilities for designing orthosteric and allosteric compounds with defined signaling properties.
Topics: Humans; Adrenergic beta-2 Receptor Agonists; Allosteric Regulation; Biosensing Techniques; Ligands; Protein Conformation; Receptors, Adrenergic, beta-2; Signal Transduction; Bioluminescence Resonance Energy Transfer Techniques
PubMed: 38127743
DOI: 10.1126/science.adh1859 -
Neuron Sep 2019Sleep is crucial for our survival, and many diseases are linked to long-term poor sleep quality. Before we can use sleep to enhance our health and performance and...
Sleep is crucial for our survival, and many diseases are linked to long-term poor sleep quality. Before we can use sleep to enhance our health and performance and alleviate diseases associated with poor sleep, a greater understanding of sleep regulation is necessary. We have identified a mutation in the β-adrenergic receptor gene in humans who require fewer hours of sleep than most. In vitro, this mutation leads to decreased protein stability and dampened signaling in response to agonist treatment. In vivo, the mice carrying the same mutation demonstrated short sleep behavior. We found that this receptor is highly expressed in the dorsal pons and that these ADRB1 neurons are active during rapid eye movement (REM) sleep and wakefulness. Activating these neurons can lead to wakefulness, and the activity of these neurons is affected by the mutation. These results highlight the important role of β-adrenergic receptors in sleep/wake regulation.
Topics: Animals; Gene Knock-In Techniques; Humans; Mice; Mutation; Neurons; Pedigree; Pontine Tegmentum; Receptors, Adrenergic, beta-1; Sleep; Sleep Wake Disorders; Sleep, REM; Wakefulness
PubMed: 31473062
DOI: 10.1016/j.neuron.2019.07.026 -
Cell Mar 2022G protein-coupled receptors (GPCRs) relay extracellular stimuli into specific cellular functions. Cells express many different GPCRs, but all these GPCRs signal to only...
G protein-coupled receptors (GPCRs) relay extracellular stimuli into specific cellular functions. Cells express many different GPCRs, but all these GPCRs signal to only a few second messengers such as cAMP. It is largely unknown how cells distinguish between signals triggered by different GPCRs to orchestrate their complex functions. Here, we demonstrate that individual GPCRs signal via receptor-associated independent cAMP nanodomains (RAINs) that constitute self-sufficient, independent cell signaling units. Low concentrations of glucagon-like peptide 1 (GLP-1) and isoproterenol exclusively generate highly localized cAMP pools around GLP-1- and β-adrenergic receptors, respectively, which are protected from cAMP originating from other receptors and cell compartments. Mapping local cAMP concentrations with engineered GPCR nanorulers reveals gradients over only tens of nanometers that define the size of individual RAINs. The coexistence of many such RAINs allows a single cell to operate thousands of independent cellular signals simultaneously, rather than function as a simple "on/off" switch.
Topics: Cell Physiological Phenomena; Cyclic AMP; Glucagon-Like Peptide 1; Receptors, Adrenergic, beta-2; Receptors, G-Protein-Coupled; Second Messenger Systems; Signal Transduction
PubMed: 35294858
DOI: 10.1016/j.cell.2022.02.011 -
Cell Jan 2020Enteric-associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility and...
Enteric-associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility and nutrient sensing. Bidirectional interactions between neuronal and immune cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated the effects of infection-induced inflammation on intrinsic EANs (iEANs) and the role of intestinal muscularis macrophages (MMs) in this context. Using murine models of enteric infections, we observed long-term gastrointestinal symptoms, including reduced motility and loss of excitatory iEANs, which was mediated by a Nlrp6- and Casp11-dependent mechanism, depended on infection history, and could be reversed by manipulation of the microbiota. MMs responded to luminal infection by upregulating a neuroprotective program via β-adrenergic receptor (β-AR) signaling and mediated neuronal protection through an arginase 1-polyamine axis. Our results identify a mechanism of neuronal death post-infection and point to a role for tissue-resident MMs in limiting neuronal damage.
Topics: Adrenergic Agents; Animals; Arginase; Caspases, Initiator; Enteric Nervous System; Female; Gastrointestinal Diseases; Gastrointestinal Microbiome; Infections; Inflammation; Intestinal Mucosa; Intestine, Small; Intestines; Macrophages; Male; Mice; Mice, Inbred C57BL; Microbiota; Neurons; Receptors, Adrenergic, beta-2; Receptors, Cell Surface; Signal Transduction
PubMed: 31923400
DOI: 10.1016/j.cell.2019.12.002 -
JCI Insight Jun 2021β3-Adrenergic receptors (β3-ARs) are the predominant regulators of rodent brown adipose tissue (BAT) thermogenesis. However, in humans, the physiological relevance of...
β3-Adrenergic receptors (β3-ARs) are the predominant regulators of rodent brown adipose tissue (BAT) thermogenesis. However, in humans, the physiological relevance of BAT and β3-AR remains controversial. Herein, using primary human adipocytes from supraclavicular neck fat and immortalized brown/beige adipocytes from deep neck fat from 2 subjects, we demonstrate that the β3-AR plays a critical role in regulating lipolysis, glycolysis, and thermogenesis. Silencing of the β3-AR compromised genes essential for thermogenesis, fatty acid metabolism, and mitochondrial mass. Functionally, reduction of β3-AR lowered agonist-mediated increases in intracellular cAMP, lipolysis, and lipolysis-activated, uncoupling protein 1-mediated thermogenic capacity. Furthermore, mirabegron, a selective human β3-AR agonist, stimulated BAT lipolysis and thermogenesis, and both processes were lost after silencing β3-AR expression. This study highlights that β3-ARs in human brown/beige adipocytes are required to maintain multiple components of the lipolytic and thermogenic cellular machinery and that β3-AR agonists could be used to achieve metabolic benefit in humans.
Topics: Adipocytes, Beige; Adipocytes, Brown; Adipose Tissue, Brown; Clavicle; Energy Metabolism; Gene Silencing; Humans; Lipolysis; Neck; Primary Cell Culture; RNA, Messenger; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Receptors, Adrenergic, beta-3; Thermogenesis; Uncoupling Protein 1
PubMed: 34100382
DOI: 10.1172/jci.insight.139160 -
The Journal of Clinical Investigation Dec 2019Catecholamines released by sympathetic nerves can activate adrenergic receptors present on nearly every cell type, including myeloid-derived suppressor cells (MDSCs)....
Catecholamines released by sympathetic nerves can activate adrenergic receptors present on nearly every cell type, including myeloid-derived suppressor cells (MDSCs). Using in vitro systems, murine tumor models in wild-type and genetically modified (β2-AR-/-) mice, and adoptive transfer approaches, we found that the degree of β2-AR signaling significantly influences MDSC frequency and survival in tumors and other tissues. It also modulates their expression of immunosuppressive molecules such as arginase-I and PD-L1 and alters their ability to suppress the proliferation of T cells. The regulatory functions of β2-AR signaling in MDSCs were also found to be dependent upon STAT3 phosphorylation. Moreover, we observed that the β2-AR-mediated increase in MDSC survival is dependent upon Fas-FasL interactions, and this is consistent with gene expression analyses, which reveal a greater expression of apoptosis-related genes in β2-AR-/- MDSCs. Our data reveal the potential of β2-AR signaling to increase the generation of MDSCs from both murine and human peripheral blood cells and that the immunosuppressive function of MDSCs can be mitigated by treatment with β-AR antagonists, or enhanced by β-AR agonists. This strongly supports the possibility that reducing stress-induced activation of β2-ARs could help to overcome immune suppression and enhance the efficacy of immunotherapy and other cancer therapies.
Topics: Animals; Immune Tolerance; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells; Neoplasms; Phosphorylation; Receptors, Adrenergic, beta-2; STAT3 Transcription Factor; Signal Transduction
PubMed: 31566578
DOI: 10.1172/JCI129502