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Nature Structural & Molecular Biology Jan 2018G-protein-coupled receptors (GPCRs) relay numerous extracellular signals by triggering intracellular signaling through coupling with G proteins and arrestins. Recent... (Review)
Review
G-protein-coupled receptors (GPCRs) relay numerous extracellular signals by triggering intracellular signaling through coupling with G proteins and arrestins. Recent breakthroughs in the structural determination of GPCRs and GPCR-transducer complexes represent important steps toward deciphering GPCR signal transduction at a molecular level. A full understanding of the molecular basis of GPCR-mediated signaling requires elucidation of the dynamics of receptors and their transducer complexes as well as their energy landscapes and conformational transition rates. Here, we summarize current insights into the structural plasticity of GPCR-G-protein and GPCR-arrestin complexes that underlies the regulation of the receptor's intracellular signaling profile.
Topics: Allosteric Site; Animals; Electron Spin Resonance Spectroscopy; GTP-Binding Proteins; Humans; Ligands; Protein Binding; Protein Domains; Protein Structure, Secondary; Receptors, G-Protein-Coupled; Signal Transduction; beta-Arrestins
PubMed: 29323277
DOI: 10.1038/s41594-017-0011-7 -
Physiological Reviews Apr 2023Calcitonin gene-related peptide (CGRP) is a neuropeptide with diverse physiological functions. Its two isoforms (α and β) are widely expressed throughout the body in... (Review)
Review
Calcitonin gene-related peptide (CGRP) is a neuropeptide with diverse physiological functions. Its two isoforms (α and β) are widely expressed throughout the body in sensory neurons as well as in other cell types, such as motor neurons and neuroendocrine cells. CGRP acts via at least two G protein-coupled receptors that form unusual complexes with receptor activity-modifying proteins. These are the CGRP receptor and the AMY receptor; in rodents, additional receptors come into play. Although CGRP is known to produce many effects, the precise molecular identity of the receptor(s) that mediates CGRP effects is seldom clear. Despite the many enigmas still in CGRP biology, therapeutics that target the CGRP axis to treat or prevent migraine are a bench-to-bedside success story. This review provides a contextual background on the regulation and sites of CGRP expression and CGRP receptor pharmacology. The physiological actions of CGRP in the nervous system are discussed, along with updates on CGRP actions in the cardiovascular, pulmonary, gastrointestinal, immune, hematopoietic, and reproductive systems and metabolic effects of CGRP in muscle and adipose tissues. We cover how CGRP in these systems is associated with disease states, most notably migraine. In this context, we discuss how CGRP actions in both the peripheral and central nervous systems provide a basis for therapeutic targeting of CGRP in migraine. Finally, we highlight potentially fertile ground for the development of additional therapeutics and combinatorial strategies that could be designed to modulate CGRP signaling for migraine and other diseases.
Topics: Humans; Calcitonin Gene-Related Peptide; Receptors, Calcitonin Gene-Related Peptide; Migraine Disorders; Central Nervous System; Motor Neurons
PubMed: 36454715
DOI: 10.1152/physrev.00059.2021 -
Methods in Molecular Biology (Clifton,... 2016The estrogen receptors, ERα, ERβ, and GPER, mediate the effects of estrogenic compounds on their target tissues. Estrogen receptors are located in the tissues of the... (Review)
Review
The estrogen receptors, ERα, ERβ, and GPER, mediate the effects of estrogenic compounds on their target tissues. Estrogen receptors are located in the tissues of the female reproductive tract and breast as one would expect, but also in tissues as diverse as bone, brain, liver, colon, skin, and salivary gland. The purpose of this discussion of the estrogen receptors is to provide a brief overview of the estrogen receptors and estrogen action from perspectives such as the historical, physiological, pharmacological, pathological, structural, and ligand perspectives.
Topics: Animals; Disease Susceptibility; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Evolution, Molecular; Female; Humans; Ligands; Male; Receptors, Estrogen; Receptors, G-Protein-Coupled; Risk Factors; Sex Factors; Signal Transduction
PubMed: 26585122
DOI: 10.1007/978-1-4939-3127-9_1 -
Immunity May 2018The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia,...
The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia, Nasu-Hakola disease, and with an increased risk of Alzheimer's disease. Microglial defects in phagocytosis of toxic aggregates or apoptotic membranes were proposed to be at the origin of the pathological processes in the presence of Trem2 inactivating mutations. Here, we show that TREM2 is essential for microglia-mediated synaptic refinement during the early stages of brain development. The absence of Trem2 resulted in impaired synapse elimination, accompanied by enhanced excitatory neurotransmission and reduced long-range functional connectivity. Trem2 mice displayed repetitive behavior and altered sociability. TREM2 protein levels were also negatively correlated with the severity of symptoms in humans affected by autism. These data unveil the role of TREM2 in neuronal circuit sculpting and provide the evidence for the receptor's involvement in neurodevelopmental diseases.
Topics: Animals; Autistic Disorder; Brain; Cells, Cultured; Humans; Membrane Glycoproteins; Mice, Inbred C57BL; Mice, Knockout; Microglia; Neurons; Receptors, Immunologic; Synapses; Synaptic Transmission
PubMed: 29752066
DOI: 10.1016/j.immuni.2018.04.016 -
Nature Sep 2021Olfactory systems must detect and discriminate amongst an enormous variety of odorants. To contend with this challenge, diverse species have converged on a common...
Olfactory systems must detect and discriminate amongst an enormous variety of odorants. To contend with this challenge, diverse species have converged on a common strategy in which odorant identity is encoded through the combinatorial activation of large families of olfactory receptors, thus allowing a finite number of receptors to detect a vast chemical world. Here we offer structural and mechanistic insight into how an individual olfactory receptor can flexibly recognize diverse odorants. We show that the olfactory receptor MhOR5 from the jumping bristletail Machilis hrabei assembles as a homotetrameric odorant-gated ion channel with broad chemical tuning. Using cryo-electron microscopy, we elucidated the structure of MhOR5 in multiple gating states, alone and in complex with two of its agonists-the odorant eugenol and the insect repellent DEET. Both ligands are recognized through distributed hydrophobic interactions within the same geometrically simple binding pocket located in the transmembrane region of each subunit, suggesting a structural logic for the promiscuous chemical sensitivity of this receptor. Mutation of individual residues lining the binding pocket predictably altered the sensitivity of MhOR5 to eugenol and DEET and broadly reconfigured the receptor's tuning. Together, our data support a model in which diverse odorants share the same structural determinants for binding, shedding light on the molecular recognition mechanisms that ultimately endow the olfactory system with its immense discriminatory capacity.
Topics: Animals; Binding Sites; Cell Line; DEET; Eugenol; Insect Proteins; Insecta; Ion Channel Gating; Ion Channels; Models, Molecular; Mutation; Odorants; Protein Binding; Protein Structure, Quaternary; Receptors, Odorant; Substrate Specificity
PubMed: 34349260
DOI: 10.1038/s41586-021-03794-8 -
Cytokine Sep 2021Cytokines are pleiotropic polypeptides that control the development of and responses mediated by immune cells. Cytokine classification predominantly relies on [1] the... (Review)
Review
Cytokines are pleiotropic polypeptides that control the development of and responses mediated by immune cells. Cytokine classification predominantly relies on [1] the target receptor(s), [2] the primary structural features of the extracellular domains of their receptors, and [3] their receptor composition. Functionally, cytokines are either pro-inflammatory or anti-inflammatory, hematopoietic colony-stimulating factors, developmental and would healing maintaining immune homeostasis. When the balance in C can form complex networks amongst themselves that may affect the homeostasis and diseases. Cytokines can affect resistance and susceptibility for many diseases and their availability in the host cytokine production and interaction is disturbed, immunopathogenesis sets in. Therefore, cytokine-targeting bispecific, and chimeric antibodies form a significant mode of immnuo-therapeutics Although the field has grown deep and wide, many areas of cytokine biology remain unknown. Here, we have reviewed these cytokines along with the organization, signaling, and functions through respective cytokine-receptor-families. Being part of the special issue on the Role of Cytokines in Leishmaniasis, this review is intended to be used as an organized primer on cytokines and not a resource for detailed discussion- for which a two-volume Handbook of cytokines is available- on each of the cytokines. Priming the readers on cytokines, we next brief the role of cytokines in Leishmaniasis. In the brief, we do not provide an account of each of the involved cytokines known to date, instead, we offer a temporal relationship between the cytokines and the progress of the infection towards the alternate outcomes- healing or non-healing- of the infection.
Topics: Animals; Cytokines; Homeostasis; Humans; Inflammation; Leishmaniasis; Receptors, Cytokine; Signal Transduction
PubMed: 33581983
DOI: 10.1016/j.cyto.2021.155458 -
Current Allergy and Asthma Reports Dec 2023Chronic spontaneous urticaria and chronic inducible urticaria (CSU/CindU) are caused by mast cell and basophil activation leading to degranulation and the release of... (Review)
Review
PURPOSEOF REVIEW
Chronic spontaneous urticaria and chronic inducible urticaria (CSU/CindU) are caused by mast cell and basophil activation leading to degranulation and the release of histamine and several other mediators. Three kinds of factors can trigger mast cells in CSU: (1) activation of stimulating receptor(s) on the mast cell membrane, (2) upregulation of certain receptor(s), and (3) intracellular dysregulation in signaling with overexpression of the spleen tyrosine kinase (SYK) or reduced activation of the inhibitory Src homology 2 (SH2)-containing inositol phosphatases (SHIP)-related pathways. In CSU, two major endotypes exist based on the primary receptor activating mechanism: type I hypersensitivity (IgE-mediated, directed against auto-allergens) and type IIb (autoimmune, via IgG autoantibodies directed against IgE or the IgE-receptor). Their treatment responses vary. We discuss in vitro and in vivo biomarkers.
RECENT FINDINGS
Patients with auto-allergic CSU have clinical characteristics that can distinguish them partly from those with autoimmune CSU. Most importantly, their disease generally presents a less aggressive course, a better response to second generation (up-dosed) antihistamines and a good response to omalizumab, if necessary. Meanwhile, autoimmune CSU/CindU patients fare less well and often need immunosuppressive drugs. Biomarkers that might help endotype CSU/CindU patients and select the most appropriate treatment, dose, and duration, e.g., for autoallergic CSU, high total IgE and IgE against auto-allergens; for autoimmune CSU, low IgE, basopenia, and IgG against autoantigens like thyroid peroxidase and a positive autologous serum skin test (but sometimes also positive in autoallergy). Some biomarkers are easily accessible but of low specificity; others are highly specific but more futuristic.
Topics: Humans; Urticaria; Immunoglobulin E; Chronic Urticaria; Biomarkers; Omalizumab; Allergens; Chronic Inducible Urticaria; Immunoglobulin G; Chronic Disease
PubMed: 38064133
DOI: 10.1007/s11882-023-01117-7 -
Frontiers in Molecular Neuroscience 2022Morphine remains the gold standard painkiller available to date to relieve severe pain. Morphine metabolism leads to the production of two predominant metabolites,... (Review)
Review
Morphine remains the gold standard painkiller available to date to relieve severe pain. Morphine metabolism leads to the production of two predominant metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). This metabolism involves uridine 5'-diphospho-glucuronosyltransferases (UGTs), which catalyze the addition of a glucuronide moiety onto the C3 or C6 position of morphine. Interestingly, M3G and M6G have been shown to be biologically active. On the one hand, M6G produces potent analgesia in rodents and humans. On the other hand, M3G provokes a state of strong excitation in rodents, characterized by thermal hyperalgesia and tactile allodynia. Its coadministration with morphine or M6G also reduces the resulting analgesia. Although these behavioral effects show quite consistency in rodents, M3G effects are much more debated in humans and the identity of the receptor(s) on which M3G acts remains unclear. Indeed, M3G has little affinity for mu opioid receptor (MOR) (on which morphine binds) and its effects are retained in the presence of naloxone or naltrexone, two non-selective MOR antagonists. Paradoxically, MOR seems to be essential to M3G effects. In contrast, several studies proposed that TLR4 could mediate M3G effects since this receptor also appears to be essential to M3G-induced hyperalgesia. This review summarizes M3G's behavioral effects and potential targets in the central nervous system, as well as the mechanisms by which it might oppose analgesia.
PubMed: 35645730
DOI: 10.3389/fnmol.2022.882443 -
Annual Review of Microbiology Sep 2016The ability of bacteria to recognize kin provides a means to form social groups. In turn these groups can lead to cooperative behaviors that surpass the ability of the... (Review)
Review
The ability of bacteria to recognize kin provides a means to form social groups. In turn these groups can lead to cooperative behaviors that surpass the ability of the individual. Kin recognition involves specific biochemical interactions between a receptor(s) and an identification molecule(s). Recognition specificity, ensuring that nonkin are excluded and kin are included, is critical and depends on the number of loci and polymorphisms involved. After recognition and biochemical perception, the common ensuing cooperative behaviors include biofilm formation, quorum responses, development, and swarming motility. Although kin recognition is a fundamental mechanism through which cells might interact, microbiologists are only beginning to explore the topic. This review considers both molecular and theoretical aspects of bacterial kin recognition. Consideration is also given to bacterial diversity, genetic relatedness, kin selection theory, and mechanisms of recognition.
Topics: Bacteria; Bacterial Physiological Phenomena; Bacterial Proteins; Gene Expression Regulation, Bacterial
PubMed: 27359217
DOI: 10.1146/annurev-micro-102215-095325