scholarly journals Modulation of the Serotonergic Receptosome in the Treatment of Anxiety and Depression: A Narrative Review of the Experimental Evidence

2021 ◽  
Vol 14 (2) ◽  
pp. 148
Author(s):  
Gustavo R. Villas-Boas ◽  
Stefânia N. Lavorato ◽  
Marina M. Paes ◽  
Pablinny M. G. de Carvalho ◽  
Vanessa C. Rescia ◽  
...  
Keyword(s):  
Experimental Evidence ◽  
Rational Design ◽  
Brain Regions ◽  
G Protein Coupled Receptors ◽  
New Drugs ◽  
Anxiety And Depression ◽  
Pharmacological Mechanism ◽  
Art Research ◽  
G Protein Coupled ◽  
The Brain

Serotonin (5-HT) receptors are found throughout central and peripheral nervous systems, mainly in brain regions involved in the neurobiology of anxiety and depression. 5-HT receptors are currently promising targets for discovering new drugs for treating disorders ranging from migraine to neuropsychiatric upsets, such as anxiety and depression. It is well described in the current literature that the brain expresses seven types of 5-HT receptors comprising eighteen distinct subtypes. In this article, we comprehensively reviewed 5-HT1-7 receptors. Of the eighteen 5-HT receptors known today, thirteen are G protein-coupled receptors (GPCRs) and represent targets for approximately 40% of drugs used in humans. Signaling pathways related to these receptors play a crucial role in neurodevelopment and can be modulated to develop effective therapies to treat anxiety and depression. This review presents the experimental evidence of the modulation of the “serotonergic receptosome” in the treatment of anxiety and depression, as well as demonstrating state-of-the-art research related to phytochemicals and these disorders. In addition, detailed aspects of the pharmacological mechanism of action of all currently known 5-HT receptor families were reviewed. From this review, it will be possible to direct the rational design of drugs towards new therapies that involve signaling via 5-HT receptors.

scholarly journals The cell biology of smell

2010 ◽  
Vol 191 (3) ◽  
pp. 443-452 ◽  
Author(s):  
Shannon DeMaria ◽  
John Ngai
Keyword(s):  
Olfactory System ◽  
Cell Biology ◽  
Odorant Receptor ◽  
Large Family ◽  
G Protein Coupled Receptors ◽  
Odorant Receptors ◽  
Chemical Structures ◽  
Wide Range ◽  
G Protein Coupled ◽  
The Brain

The olfactory system detects and discriminates myriad chemical structures across a wide range of concentrations. To meet this task, the system utilizes a large family of G protein–coupled receptors—the odorant receptors—which are the chemical sensors underlying the perception of smell. Interestingly, the odorant receptors are also involved in a number of developmental decisions, including the regulation of their own expression and the patterning of the olfactory sensory neurons' synaptic connections in the brain. This review will focus on the diverse roles of the odorant receptor in the function and development of the olfactory system.

Transmembrane Signaling in the Brain by Serotonin, A Key Regulator of Physiology and Emotion

2005 ◽  
Vol 25 (5-6) ◽  
pp. 363-385 ◽  
Author(s):  
Tatyana Adayev ◽  
Buddima Ranasinghe ◽  
Probal Banerjee
Keyword(s):  
Gene Expression ◽  
Immune Cells ◽  
Functional Role ◽  
Living Organism ◽  
Covalent Modification ◽  
G Protein Coupled Receptors ◽  
And Behavior ◽  
G Protein Coupled ◽  
Compare And Contrast ◽  
The Brain

Serotonin (5-HT) is an ancient chemical that plays a crucial functional role in almost every living organism. It regulates platelet aggregation, activation of immune cells, and contraction of stomach and intestinal muscles. In addition, serotonin acts as a neurotransmitter in the brain and the peripheral nervous system. These activities are initiated by the binding of serotonin to 15 or more receptors that are pharmacologically classified into seven groups, 5-HT1 through 5-HT7. Each group is further divided into subgroups of receptors that are homologous but are encoded by discrete genes. With the exception of the 5-HT3 receptor-a cation channel—all of the others are G protein-coupled receptors that potentially activate or inhibit a large number of biochemical cascades. This review will endeavor to compare and contrast such signaling pathways with special attention to their tissue-specific occurrence, their possible role in immediate effects on covalent modification of other proteins, and relatively slower effects on gene expression, physiology and behavior.

scholarly journals Effect of 5-hydroxytryptamine Receptor in the Lower Esophageal Sphincter Regulation Mechanism

2020 ◽  
Vol 3 (6) ◽  
Author(s):  
Hefei Li ◽  
Junfeng Liu ◽  
Xixuan Zhang ◽  
Zhiwei Lai ◽  
Zhen Gao ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Regulation Mechanism ◽  
Visceral Sensitivity ◽  
Gastrointestinal Dysfunction ◽  
Secretion Regulation ◽  
The Central Nervous System ◽  
Esophageal Sphincter ◽  
G Protein Coupled ◽  
The Brain

As a neurotransmitter and avascular active substance, the 5-hydroxytryptamine (5-HT, serotonin) is widely distributed in the central nervous system and surrounding tissues. The 5-HT can play its role by acting on its corresponding 5-HT receptor. Nowadays, the 5-HT receptor can be classified into seven, according to different signal transduction method of receptors, the 5-HT3 receptor belongs to the ligand-gated ion channels, while other six 5-HT receptors are involved into the G protein-coupled receptors and play the biological role by binding to specific G protein-coupled receptors (GPCRs) on the surface of the cell membrane. The 5-HT plays an important role in the brain-gut information transmission and studies showed that the physiological stimulations like having meals, and pathological stimulations like ischemia and stress could promote the release of the 5-HT. In the gastrointestinal tract, the 5-HT is closely related to gastrointestinal sensitivity, gastrointestinal movement and secretion regulation, as well as many gastrointestinal dysfunction disorders, such as gastrointestinal power and visceral sensitivity abnormality and abnormalities of brain-gut axis.

scholarly journals Melatonin

2002 ◽  
Vol 4 (1) ◽  
pp. 57-72 ◽  
Keyword(s):  
Seasonal Affective Disorder ◽  
Physiological Role ◽  
G Protein Coupled Receptors ◽  
The Body ◽  
Receptor Subtypes ◽  
Seasonal Breeding ◽  
Livestock Management ◽  
G Protein Coupled ◽  
The Brain ◽  
Melatonin Production

Melatonin (MEL) is a hormone synthesized and secreted by the pineal gland deep within the brain in response to photoperiodic cues relayed from the retina via an endogenous circadian oscillator within the suprachiasmatic nucleus in the hypothalamus. The circadian rhythm of melatonin production and release, characterized by nocturnal activity and daytime quiescence, is an important temporal signal to the body structures that can read it. Melatonin acts through high-affinity receptors located centrally and in numerous peripheral organs. Different receptor subtypes have been cloned and characterized: MT(1) and MT(2) (transmembrane G-protein-coupled receptors), and MT(3). However, their physiological role remains unelucidated, although livestock management applications already include the control of seasonal breeding and milk production. As for potential therapeutic applications, exogenous melatonin or a melatonin agonist and selective 5-hydroxytrypiamine receptor (5-HT(2c)) antagonist, eg, S 20098, can be used to manipulate circadian processes such as the sleep-vake cycle, which are frequently disrupted in many conditions, most notably seasonal affective disorder.

scholarly journals Unique Features of Different Classes of G-Protein-Coupled Receptors Revealed from Sequence Coevolutionary and Structural Analysis

2021 ◽  
Author(s):  
Hung Do ◽  
Allan Haldane ◽  
Ronald M. Levy ◽  
Yinglong Miao
Keyword(s):  
G Protein ◽  
Rational Design ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Class A ◽  
Gpcr Activation ◽  
Residue Contacts ◽  
Critical Residue ◽  
Contact Frequency ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and represent the primary targets of about one third of currently marketed drugs. Despite the critical importance, experimental structures have been determined for only a limited portion of GPCRs and functional mechanisms of GPCRs remain poorly understood. Here, we have constructed novel sequence coevolutionary models of the A and B classes of GPCRs and compared them with residue contact frequency maps generated with available experimental structures. Significant portions of structural residue contacts were successfully detected in the sequence-based covariational models. “Exception” residue contacts predicted from sequence coevolutionary models but not available structures added missing links that were important for GPCR activation and allosteric modulation. Moreover, we identified distinct residue contacts involving different sets of functional motifs for GPCR activation, such as the Na+ pocket, CWxP, DRY, PIF and NPxxY motifs in the class A and the HETx and PxxG motifs in the class B. Finally, we systematically uncovered critical residue contacts tuned by allosteric modulation in the two classes of GPCRs, including those from the activation motifs and particularly the extracellular and intracellular loops in class A GPCRs. These findings provide a promising framework for rational design of ligands to regulate GPCR activation and allosteric modulation.

scholarly journals The Role of Urocortins in Intracerebral Hemorrhage

Biomolecules ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 96 ◽  
Author(s):  
Ker Woon Choy ◽  
Andy Po-Yi Tsai ◽  
Peter Bor-Chian Lin ◽  
Meng-Yu Wu ◽  
Chihyi Lee ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Brain Regions ◽  
Brain Parenchyma ◽  
Protective Mechanisms ◽  
Neuroprotective Effects ◽  
Blood Brain Barrier Disruption ◽  
Brain Barrier Disruption ◽  
G Protein Coupled ◽  
The Brain

Intracerebral hemorrhage (ICH) causes an accumulation of blood in the brain parenchyma that disrupts the normal neurological function of the brain. Despite extensive clinical trials, no medical or surgical therapy has shown to be effective in managing ICH, resulting in a poor prognosis for the patients. Urocortin (UCN) is a 40-amino-acid endogenous neuropeptide that belongs to the corticotropin-releasing hormone (CRH) family. The effect of UCN is activated by binding to two G-protein coupled receptors, CRH-R1 and CRH-R2, which are expressed in brain neurons and glial cells in various brain regions. Current research has shown that UCN exerts neuroprotective effects in ICH models via anti-inflammatory effects, which generally reduced brain edema and reduced blood-brain barrier disruption. These effects gradually help in the improvement of the neurological outcome, and thus, UCN may be a potential therapeutic target in the treatment of ICH. This review summarizes the data published to date on the role of UCN in ICH and the possible protective mechanisms underlined.

Complementary roles of mouse lipocalins in chemical communication and immunity

2014 ◽  
Vol 42 (4) ◽  
pp. 893-898 ◽  
Author(s):  
Romana Stopková ◽  
Barbora Dudková ◽  
Petra Hájková ◽  
Pavel Stopka
Keyword(s):  
Oral Cavity ◽  
G Protein ◽  
Primary Site ◽  
G Protein Coupled Receptors ◽  
Main Route ◽  
Evolutionary Forces ◽  
Biochemical Pathways ◽  
G Protein Coupled ◽  
The Brain ◽  
Exogenous Substances

A primary site of infection in mammals is the nostrils, representing the gate to the brain through olfactory and vomeronasal epithelia, eyes as a direct route to the brain via the optical nerve, and oral cavity representing the main route to the digestive tract. Similarly, pheromones, odorants and tastants enter animal bodies the same way. Therefore similar evolutionary forces might have shaped the evolution of systems for recognition of pathogens and chemical signals. This might have resulted in sharing various proteins among systems of recognition and filtering to decrease potential costs of evolving and utilizing unique biochemical pathways. This has been documented previously in, for example, multipurpose and widely distributed GPCRs (G-protein-coupled receptors). The aim of the present review is to explore potential functional overlaps or complementary functions of lipocalins in the system of perception of exogenous substances to reconstruct the evolutionary forces that might have shaped their synergistic functions.

How ligands and signalling proteins affect G-protein-coupled receptors' conformational landscape

2013 ◽  
Vol 41 (1) ◽  
pp. 144-147 ◽  
Author(s):  
Sophie Mary ◽  
Jean-Alain Fehrentz ◽  
Marjorie Damian ◽  
Pascal Verdié ◽  
Jean Martinez ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Effector Proteins ◽  
New Drugs ◽  
Signalling Pathways ◽  
Ghrelin Receptor ◽  
Multiple Data ◽  
Conformational Landscape ◽  
G Protein Coupled ◽  
Receptor Conformation

The dynamic character of GPCRs (G-protein-coupled receptors) is essential to their function. However, the details of how ligands and signalling proteins stabilize a receptor conformation to trigger the activation of a given signalling pathway remain largely unexplored. Multiple data, including recent results obtained with the purified ghrelin receptor, suggest a model where ligand efficacy and functional selectivity are directly related to different receptor conformations. Importantly, distinct effector proteins (G-proteins and arrestins) as well as ligands are likely to affect the conformational landscape of GPCRs in different manners, as we show with the isolated ghrelin receptor. Such modulation of the GPCR conformational landscape by pharmacologically distinct ligands and effector proteins has major implications for the design of new drugs that activate specific signalling pathways.

scholarly journals Opposing roles of primate areas 25 and 32 and their putative rodent homologs in the regulation of negative emotion

2017 ◽  
Vol 114 (20) ◽  
pp. E4075-E4084 ◽  
Author(s):  
Chloe U. Wallis ◽  
Rudolf N. Cardinal ◽  
Laith Alexander ◽  
Angela C. Roberts ◽  
Hannah F. Clarke
Keyword(s):  
Negative Emotion ◽  
Brain Regions ◽  
Emotional Dysregulation ◽  
Anxiety And Depression ◽  
Depression And Anxiety ◽  
Behavioral Correlates ◽  
The Brain ◽  
Insight Into ◽  
Human Neuroimaging

Disorders of dysregulated negative emotion such as depression and anxiety also feature increased cardiovascular mortality and decreased heart-rate variability (HRV). These disorders are correlated with dysfunction within areas 25 and 32 of the ventromedial prefrontal cortex (vmPFC), but a causal relationship between dysregulation of these areas and such symptoms has not been demonstrated. Furthermore, cross-species translation is limited by inconsistent findings between rodent fear extinction and human neuroimaging studies of negative emotion. To reconcile these literatures, we applied an investigative approach to the brain–body interactions at the core of negative emotional dysregulation. We show that, in marmoset monkeys (a nonhuman primate that has far greater vmPFC homology to humans than rodents), areas 25 and 32 have causal yet opposing roles in regulating the cardiovascular and behavioral correlates of negative emotion. In novel Pavlovian fear conditioning and extinction paradigms, pharmacological inactivation of area 25 decreased the autonomic and behavioral correlates of negative emotion expectation, whereas inactivation of area 32 increased them via generalization. Area 25 inactivation also increased resting HRV. These findings are inconsistent with current theories of rodent/primate prefrontal functional similarity, and provide insight into the role of these brain regions in affective disorders. They demonstrate that area 32 hypoactivity causes behavioral generalization relevant to anxiety, and that area 25 is a causal node governing the emotional and cardiovascular symptomatology relevant to anxiety and depression.

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