scholarly journals Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Nicole Scholz ◽  
Chonglin Guan ◽  
Matthias Nieberler ◽  
Alexander Grotemeyer ◽  
Isabella Maiellaro ◽  
...  
Keyword(s):  
Brain Function ◽  
Direct Evidence ◽  
G Protein Coupled Receptors ◽  
Mechanical Stimuli ◽  
Ionotropic Receptor ◽  
Immunological Responses ◽  
Molecular Sensor ◽  
G Protein Coupled ◽  
Camp Levels ◽  
Receptor Family

Adhesion-type G protein-coupled receptors (aGPCRs), a large molecule family with over 30 members in humans, operate in organ development, brain function and govern immunological responses. Correspondingly, this receptor family is linked to a multitude of diverse human diseases. aGPCRs have been suggested to possess mechanosensory properties, though their mechanism of action is fully unknown. Here we show that the Drosophila aGPCR Latrophilin/dCIRL acts in mechanosensory neurons by modulating ionotropic receptor currents, the initiating step of cellular mechanosensation. This process depends on the length of the extended ectodomain and the tethered agonist of the receptor, but not on its autoproteolysis, a characteristic biochemical feature of the aGPCR family. Intracellularly, dCIRL quenches cAMP levels upon mechanical activation thereby specifically increasing the mechanosensitivity of neurons. These results provide direct evidence that the aGPCR dCIRL acts as a molecular sensor and signal transducer that detects and converts mechanical stimuli into a metabotropic response.

scholarly journals Adhesion GPCRs in Glioblastoma

2021 ◽  
Author(s):  
Gabriele Stephan ◽  
Niklas Ravn-Boess ◽  
Dimitris G Placantonakis
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
The Past ◽  
Novel Treatment ◽  
The Family ◽  
Health And Disease ◽  
Basic Biology ◽  
G Protein Coupled ◽  
Potential Use ◽  
Receptor Family

Abstract Members of the adhesion family of G protein-coupled receptors (GPCRs) have received attention for their roles in health and disease, including cancer. Over the past decade, several members of the family have been implicated in the pathogenesis of glioblastoma. Here, we discuss the basic biology of adhesion GPCRs and review in detail specific members of the receptor family with known functions in glioblastoma. Finally, we discuss the potential use of adhesion GPCRs as novel treatment targets in neuro-oncology.

scholarly journals cAMP levels regulate macrophage alternative activation marker expression

2020 ◽  
pp. 175342592097508
Author(s):  
Swamy Polumuri ◽  
Darren J Perkins ◽  
Stefanie N Vogel
Keyword(s):  
G Protein Coupled Receptors ◽  
Alternative Activation ◽  
Marker Genes ◽  
Marker Expression ◽  
Inflammatory Milieu ◽  
G Protein Coupled ◽  
Camp Levels ◽  
Dependent Pathway

The capacity for macrophages to polarize into distinct functional activation states (e.g., M1, M2) is critical to tune an inflammatory response to the relevant infection or injury. Alternative or M2 polarization of macrophages is most often achieved in vitro in response to IL-4/IL-13 and results in the transcriptional up-regulation of a constellation of characteristic M2 marker genes. In vivo, additional signals from the inflammatory milieu can further increase or decrease M2 marker expression. Particularly, activation of cAMP-generating G protein-coupled receptors is reported to increase M2 markers, but whether this is strictly dependent upon cAMP production is unclear. We report herein that increased cAMP alone can increase IL-4-dependent M2 marker expression through a PKA/C/EBPβ/CREB dependent pathway in murine macrophages.

scholarly journals Basic Opioid Pharmacology — An Update

2020 ◽  
Vol 14 (2) ◽  
pp. 115-121 ◽  
Author(s):  
Arul James ◽  
John Williams
Keyword(s):  
Opioid Receptors ◽  
The United States ◽  
Opioid Use Disorder ◽  
G Protein Coupled Receptors ◽  
Opioid Use ◽  
Synthetic Compounds ◽  
Analgesic Agents ◽  
National Emergency ◽  
G Protein Coupled ◽  
Receptor Family

Opioids are a group of analgesic agents commonly used in clinical practice. The three classical opioid receptors are MOP, DOP and KOP. The NOP (N/OFQ) receptor is considered to be a non-opioid branch of the opioid receptor family. Opioid receptors are G-protein-coupled receptors which cause cellular hyperpolarisation when bound to opioid agonists. Opioids may be classified according to their mode of synthesis into alkaloids, semi-synthetic and synthetic compounds. Opioid use disorder (OUD) is an emerging issue and important lessons can be learnt from the United States where opioid epidemic was declared as a national emergency in 2017.

scholarly journals Specificity and nanomolar potency of melatonin on G-protein coupled melatonin MT1 and MT2 receptors expressed in HEK-293T human embryo kidney cells

2019 ◽  
Vol 2 (4) ◽  
pp. 121-131 ◽  
Author(s):  
Rafael Rivas-Santisteban ◽  
Irene Reyes-Resina ◽  
Iu Raich ◽  
Jesus J Pintor ◽  
Hanan Awad Alkozi ◽  
...  
Keyword(s):  
G Protein ◽  
Standard Procedure ◽  
G Protein Coupled Receptors ◽  
Prolonged Release ◽  
Therapeutic Effects ◽  
Selective Agonist ◽  
Human Embryo Kidney ◽  
G Protein Coupled ◽  
Camp Levels ◽  
Nanomolar Range

This is a pre-registered study, i.e. a study whose hypotheses and experiments designed to address these hypotheses have been deposited in a database before starting the experiments. The study aims at assessing the Gs versus Gi coupling and the potency of melatonin in the human version of melatonin MT1 and MT2 G-protein-coupled receptors expressed in HEK-293T cells. The results show that these receptors are Gi but not Gs coupled. By using a standard procedure of modulation of 0.5 µM forskolin-induced cAMP levels, it was found that the potency on MT2 receptor-mediated actions is in the low nanomolar range, but the potency on MT1 receptor is in the high nanomolar range.  The potency of melatonin to stimulate the MT2 receptor is similar to that of a selective agonist, N-[2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl)ethyl]butanamide (IIK7). Overall, the data on the potency of melatonin on its receptors will provide a new look for melatonin research. It is important to consider this finding for appropriately addressing physiological or therapeutic effects based on melatonin potency. Thus, the low doses of melatonin used in the existing prolonged release preparations or in other supplements should be revisited.  

scholarly journals Potential Utility of Biased GPCR Signaling for Treatment of Psychiatric Disorders

2019 ◽  
Vol 20 (13) ◽  
pp. 3207 ◽  
Author(s):  
Hidetoshi Komatsu ◽  
Mamoru Fukuchi ◽  
Yugo Habata
Keyword(s):  
Psychiatric Disorders ◽  
Signaling Pathways ◽  
Brain Function ◽  
Marked Reduction ◽  
G Protein Coupled Receptors ◽  
Detailed Understanding ◽  
Gpcr Signaling ◽  
Downstream Signaling ◽  
Multiple Signaling ◽  
G Protein Coupled

Tremendous advances have been made recently in the identification of genes and signaling pathways associated with the risks for psychiatric disorders such as schizophrenia and bipolar disorder. However, there has been a marked reduction in the pipeline for the development of new psychiatric drugs worldwide, mainly due to the complex causes that underlie these disorders. G-protein coupled receptors (GPCRs) are the most common targets of antipsychotics such as quetiapine and aripiprazole, and play pivotal roles in controlling brain function by regulating multiple downstream signaling pathways. Progress in our understanding of GPCR signaling has opened new possibilities for selective drug development. A key finding has been provided by the concept of biased ligands, which modulate some, but not all, of a given receptor’s downstream signaling pathways. Application of this concept raises the possibility that the biased ligands can provide therapeutically desirable outcomes with fewer side effects. Instead, this application will require a detailed understanding of the mode of action of antipsychotics that drive distinct pharmacologies. We review our current understanding of the mechanistic bases for multiple signaling modes by antipsychotics and the potential of the biased modulators to treat mental disorders.

scholarly journals Drug Repurposing on G Protein-Coupled Receptors Using a Computational Profiling Approach

2021 ◽  
Vol 8 ◽  
Author(s):  
Alessandra de Felice ◽  
Simone Aureli ◽  
Vittorio Limongelli
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Chemical Properties ◽  
Drug Repurposing ◽  
G Protein Coupled Receptors ◽  
Alignment Algorithm ◽  
Binding Interaction ◽  
Wide Range ◽  
G Protein Coupled ◽  
Receptor Family

G protein-coupled receptors (GPCRs) are the largest human membrane receptor family regulating a wide range of cell signaling. For this reason, GPCRs are highly desirable drug targets, with approximately 40% of prescribed medicines targeting a member of this receptor family. The structural homology of GPCRs and the broad spectrum of applications of GPCR-acting drugs suggest an investigation of the cross-activity of a drug toward different GPCR receptors with the aim of rationalizing drug side effects, designing more selective and less toxic compounds, and possibly proposing off-label therapeutic applications. Herein, we present an original in silico approach named “Computational Profiling for GPCRs” (CPG), which is able to represent, in a one-dimensional (1D) string, the physico-chemical properties of a ligand–GPCR binding interaction and, through a tailored alignment algorithm, repurpose the ligand for a different GPCR. We show three case studies where docking calculations and pharmacological data confirm the drug repurposing findings obtained through CPG on 5-hydroxytryptamine receptor 2B, beta-2 adrenergic receptor, and M2 muscarinic acetylcholine receptor. The CPG code is released as a user-friendly graphical user interface with numerous options that make CPG a powerful tool to assist the drug design of GPCR ligands.

scholarly journals Structure-guided optimization of light-activated chimeric G-protein coupled receptors

2021 ◽  
Author(s):  
Alexandra-Madelaine Tichy ◽  
Wang Lok So ◽  
Elliot Gerrard ◽  
Harald Janovjak
Keyword(s):  
G Protein ◽  
Protein Complexes ◽  
G Protein Coupled Receptors ◽  
Design Strategies ◽  
Core Domain ◽  
Chimeric Receptors ◽  
Downstream Signaling ◽  
Rational Engineering ◽  
G Protein Coupled ◽  
Receptor Family

G-protein coupled receptors (GPCRs) are the largest human receptor family and involved in virtually every physiological process. One hallmark of GPCR function is the specific coupling of activated receptors to selected downstream signaling pathways. The ability to tune this coupling would permit the development of receptors with new capabilities. GPCRs and G-proteins have been recently resolved structurally at high resolution, but this information was in only very few cases harnessed for a rational engineering of these protein complexes. Here, we demonstrate the structure-guided optimization of coupling in chimeric light-activated GPCRs (OptoXRs). Our hypothesis was that the incorporation of structural GPCR-Gα contacts will lead to improved receptor activity. We first evaluated structure-based alignments as complements to existing sequence-based methods for generation of chimeric receptors. We then show in a prototypical light-activated β2AR that inclusion of α-helical residues forming structural contacts to Gα resulted in receptors with 7- to 20-fold increased function compared to other design strategies. In turn, elimination of GPCR-Gα contacts diminished function. Finally, the efficient receptor design served as a platform for the optimization of a further light-activated receptor and spectral tuning of the photoreceptor core domain. Our work exemplifies how increased OptoXR potency and new functionalities can be achieved through structure-based design towards targeted inputs into cells and cellular networks.

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