scholarly journals The GABAB Receptor—Structure, Ligand Binding and Drug Development

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 3093
Author(s):  
Linn Samira Mari Evenseth ◽  
Mari Gabrielsen ◽  
Ingebrigt Sylte
Keyword(s):  
Transmembrane Domain ◽  
Gabab Receptor ◽  
Inhibitory Neurotransmitter ◽  
Receptor Structure ◽  
Future Drug ◽  
The Central Nervous System ◽  
Broad Variety ◽  
Structural Mechanisms ◽  
Anxiety Depression ◽  
G Protein Coupled

The γ-aminobutyric acid (GABA) type B receptor (GABAB-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABAA receptor, the receptor mediates the neurotransmission of GABA, the main inhibitory neurotransmitter in the central nervous system (CNS). In recent decades, the receptor has been extensively studied with the intention being to understand pathophysiological roles, structural mechanisms and develop drugs. The dysfunction of the receptor is linked to a broad variety of disorders, including anxiety, depression, alcohol addiction, memory and cancer. Despite extensive efforts, few compounds are known to target the receptor, and only the agonist baclofen is approved for clinical use. The receptor is a mandatory heterodimer of the GABAB1 and GABAB2 subunits, and each subunit is composed of an extracellular Venus Flytrap domain (VFT) and a transmembrane domain of seven α-helices (7TM domain). In this review, we briefly present the existing knowledge about the receptor structure, activation and compounds targeting the receptor, emphasizing the role of the receptor in previous and future drug design and discovery efforts.

scholarly journals Molecular mechanisms of metabotropic GABAB receptor function

2021 ◽  
Vol 7 (22) ◽  
pp. eabg3362
Author(s):  
Hamidreza Shaye ◽  
Benjamin Stauch ◽  
Cornelius Gati ◽  
Vadim Cherezov
Keyword(s):  
G Protein ◽  
Molecular Mechanisms ◽  
Gabab Receptor ◽  
Neurological Diseases ◽  
Activation Mechanism ◽  
Allosteric Modulators ◽  
Inhibitory Neurotransmitter ◽  
Therapeutic Drugs ◽  
G Protein Coupled ◽  
The Brain

Metabotropic γ-aminobutyric acid G protein–coupled receptors (GABAB) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABAB. Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABAB receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.

scholarly journals Targeting the 5-HT2C Receptor in Biological Context and the Current State of 5-HT2C Receptor Ligand Development

2019 ◽  
Vol 19 (16) ◽  
pp. 1381-1398 ◽  
Author(s):  
Eric A. Wold ◽  
Christopher T. Wild ◽  
Kathryn A. Cunningham ◽  
Jia Zhou
Keyword(s):  
Biological Significance ◽  
Current Status ◽  
Allosteric Modulators ◽  
Class A ◽  
Current State ◽  
The Central Nervous System ◽  
Treatment Of Obesity ◽  
And Function ◽  
Anxiety Depression ◽  
G Protein Coupled

Serotonin (5-HT) 5-HT2C receptor (5-HT2CR) is recognized as a critical mediator of diseaserelated pathways and behaviors based upon actions in the central nervous system (CNS). Since 5-HT2CR is a class A G protein-coupled receptor (GPCR), drug discovery efforts have traditionally pursued the activation of the receptor through synthetic ligands with agonists proposed for the treatment of obesity, substance use disorders and impulse control disorders while antagonists may add value for the treatment of anxiety, depression and schizophrenia. The most significant agonist discovery to date is the FDAapproved anti-obesity medication lorcaserin. In recent years, efforts towards developing other mechanisms to enhance receptor function have resulted in the discovery of Positive Allosteric Modulators (PAMs) for the 5-HT2CR, with several molecule series now reported. The biological significance and context for signaling and function of the 5-HT2CR, and the current status of 5-HT2CR agonists and PAMs are discussed in this review.

scholarly journals Crocus sativus L. Extracts and Its Constituents Crocins and Safranal; Potential Candidates for Schizophrenia Treatment?

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1237
Author(s):  
Nikolaos Pitsikas
Keyword(s):  
Antipsychotic Agents ◽  
Crocus Sativus ◽  
Current Therapy ◽  
Bioactive Components ◽  
Memory Problems ◽  
Beneficial Action ◽  
The Central Nervous System ◽  
Anxiety Depression ◽  
New Antipsychotics ◽  
Crocus Sativus L

Schizophrenia is a chronic mental devastating disease. Current therapy suffers from various limitations including low efficacy and serious side effects. Thus, there is an urgent necessity to develop new antipsychotics with higher efficacy and safety. The dried stigma of the plant Crocus sativus L., (CS) commonly known as saffron, are used in traditional medicine for various purposes. It has been demonstrated that saffron and its bioactive components crocins and safranal exert a beneficial action in different pathologies of the central nervous system such as anxiety, depression, epilepsy and memory problems. Recently, their role as potential antipsychotic agents is under investigation. In the present review, I intended to critically assess advances in research of these molecules for the treatment of schizophrenia, comment on their advantages over currently used neuroleptics as well-remaining challenges. Up to our days, few preclinical studies have been conducted to this end. In spite of it, results are encouraging and strongly corroborate that additional research is mandatory aiming to definitively establish a role for saffron and its bioactive components for the treatment of schizophrenia.

scholarly journals Prohibitin: A Novel Molecular Player in KDEL Receptor Signalling

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Monica Giannotta ◽  
Giorgia Fragassi ◽  
Antonio Tamburro ◽  
Capone Vanessa ◽  
Alberto Luini ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Golgi Complex ◽  
Membrane Trafficking ◽  
Transmembrane Domain ◽  
Cell Cycle Control ◽  
Retrograde Transport ◽  
Multifunctional Protein ◽  
G Protein Coupled ◽  
Kdel Receptor ◽  
Prohibitin 1

The KDEL receptor (KDELR) is a seven-transmembrane-domain protein involved in retrograde transport of protein chaperones from the Golgi complex to the endoplasmic reticulum. Our recent findings have shown that the Golgi-localised KDELR acts as a functional G-protein-coupled receptor by binding to and activating Gs and Gq. These G proteins induce activation of PKA and Src and regulate retrograde and anterograde Golgi trafficking. Here we used an integrated coimmunoprecipitation and mass spectrometry approach to identify prohibitin-1 (PHB) as a KDELR interactor. PHB is a multifunctional protein that is involved in signal transduction, cell-cycle control, and stabilisation of mitochondrial proteins. We provide evidence that depletion of PHB induces intense membrane-trafficking activity at the ER–Golgi interface, as revealed by formation of GM130-positive Golgi tubules, and recruitment of p115,β-COP, and GBF1 to the Golgi complex. There is also massive recruitment of SEC31 to endoplasmic-reticulum exit sites. Furthermore, absence of PHB decreases the levels of the Golgi-localised KDELR, thus preventing KDELR-dependent activation of Golgi-Src and inhibiting Golgi-to-plasma-membrane transport of VSVG. We propose a model whereby in analogy to previous findings (e.g., the RAS-RAF signalling pathway), PHB can act as a signalling scaffold protein to assist in KDELR-dependent Src activation.

scholarly journals Trans-Activation of Mutant Follicle-Stimulating Hormone Receptors Selectively Generates Only One of Two Hormone Signals

2004 ◽  
Vol 18 (4) ◽  
pp. 968-978 ◽  
Author(s):  
Inhae Ji ◽  
ChangWoo Lee ◽  
MyoungKun Jeoung ◽  
YongBum Koo ◽  
Gail A. Sievert ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
G Protein ◽  
Hormone Receptors ◽  
Transmembrane Domain ◽  
Signal Generation ◽  
Lh Receptor ◽  
Glycosyl Phosphatidylinositol ◽  
Mutant Receptors ◽  
G Protein Coupled ◽  
Hormone Signals

Abstract Previously, we reported that a liganded LH receptor (LHR) is capable of activating itself (cis-activation) and other nonliganded LHRs to induce cAMP (trans-activation). Trans-activation of the LHR raises two crucial questions. Is trans-activation unique to LHR or common to other G protein-coupled receptors? Does trans-activation stimulate phospholipase Cβ as it does adenylyl cyclase? To address these questions, two types of novel FSH receptors (FSHRs) were constructed, one defective in hormone binding and the other defective in signal generation. The FSHR, a G protein-coupled receptor, comprises two major domains, the N-terminal extracellular exodomain that binds the hormone and the membrane-associated endodomain that generates the hormone signals. For signal defective receptors, the exodomain was attached to glycosyl phosphatidylinositol (ExoGPI) or the transmembrane domain of CD8 immune receptor (ExoCD). ExoGPI and ExoCD can trans-activate another nonliganded FSH. Surprisingly, the trans-activation generates a signal to activate either adenylyl cyclase or phospholipase Cβ, but not both. These results indicate that trans-activation in these mutant receptors is selective and limited in signal generation, thus providing new approaches to investigating the generation of different hormone signals and a novel means to selectively generate a particular hormone signal. Our data also suggest that the FSHR’s exodomain could not trans-activate LHR.

scholarly journals The Role of Prokineticin 2 in Oxidative Stress and in Neuropathological Processes

2021 ◽  
Vol 12 ◽  
Author(s):  
Roberta Lattanzi ◽  
Cinzia Severini ◽  
Daniela Maftei ◽  
Luciano Saso ◽  
Aldo Badiani
Keyword(s):  
Pain Perception ◽  
G Protein Coupled Receptors ◽  
Cellular Processes ◽  
Prokineticin 2 ◽  
Physiological Processes ◽  
Pathological Conditions ◽  
Double Function ◽  
The Central Nervous System ◽  
G Protein Coupled

The prokineticin (PK) family, prokineticin 1 and Bv8/prokineticin 2 (PROK2), initially discovered as regulators of gastrointestinal motility, interacts with two G protein-coupled receptors, PKR1 and PKR2, regulating important biological functions such as circadian rhythms, metabolism, angiogenesis, neurogenesis, muscle contractility, hematopoiesis, immune response, reproduction and pain perception. PROK2 and PK receptors, in particular PKR2, are widespread distributed in the central nervous system, in both neurons and glial cells. The PROK2 expression levels can be increased by a series of pathological insults, such as hypoxia, reactive oxygen species, beta amyloid and excitotoxic glutamate. This suggests that the PK system, participating in different cellular processes that cause neuronal death, can be a key mediator in neurological/neurodegenerative diseases. While many PROK2/PKRs effects in physiological processes have been documented, their role in neuropathological conditions is not fully clarified, since PROK2 can have a double function in the mechanisms underlying to neurodegeneration or neuroprotection. Here, we briefly outline the latest findings on the modulation of PROK2 and its cognate receptors following different pathological insults, providing information about their opposite neurotoxic and neuroprotective role in different pathological conditions.

scholarly journals Physiology of the orexinergic/hypocretinergic system: a revisit in 2012

2013 ◽  
Vol 304 (1) ◽  
pp. C2-C32 ◽  
Author(s):  
Jyrki P. Kukkonen
Keyword(s):  
Central Nervous System ◽  
G Proteins ◽  
Cellular Responses ◽  
G Protein Coupled Receptors ◽  
Heterotrimeric G Proteins ◽  
Neuronal Excitation ◽  
System A ◽  
The Central Nervous System ◽  
G Protein Coupled ◽  
Systemic Responses

The neuropeptides orexins and their G protein-coupled receptors, OX1and OX2, were discovered in 1998, and since then, their role has been investigated in many functions mediated by the central nervous system, including sleep and wakefulness, appetite/metabolism, stress response, reward/addiction, and analgesia. Orexins also have peripheral actions of less clear physiological significance still. Cellular responses to the orexin receptor activity are highly diverse. The receptors couple to at least three families of heterotrimeric G proteins and other proteins that ultimately regulate entities such as phospholipases and kinases, which impact on neuronal excitation, synaptic plasticity, and cell death. This article is a 10-year update of my previous review on the physiology of the orexinergic/hypocretinergic system. I seek to provide a comprehensive update of orexin physiology that spans from the molecular players in orexin receptor signaling to the systemic responses yet emphasizing the cellular physiological aspects of this system.

Pain and Comorbid Psychiatric Illnesses in Elderly People

2020 ◽  
pp. 291-302
Author(s):  
Mellar P. Davis ◽  
John L. Shuster
Keyword(s):  
Elderly People ◽  
Close Association ◽  
Physiological Changes ◽  
Analgesic Tolerance ◽  
Psychiatric Illnesses ◽  
Self Rated Health ◽  
The Central Nervous System ◽  
Anxiety Depression ◽  
The Relationship ◽  
Single Question

Chronic pain is often associated with anxiety, depression, and frailty. The relationship between pain and mental illness is complex and bidirectional. In elderly people, poor self-rated health is strongly associated with pain severity, and pain-related interference with daily activities leads to depression. There is a shared neural substrate within the central nervous system (CNS) between pain and depression, which have a common neuroanatomical organization within the CNS. The close association between pain and depression means that assessment of pain should be accompanied by assessment of depression even if by the single question, “Are you depressed?” The physiological changes in aging influence the pain experience and analgesic tolerance, which diminishes in the presence of comorbidities. Tolerance to antidepressants is also diminished, with a greater risk for drug–drug interactions due to polypharmacy, which accompanies older age.

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