G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

Azam, Shofiul; Haque, Md. Ezazul; Jakaria, Md.; Jo, Song-Hee; Kim, In-Su; Choi, Dong‐Kug

doi:10.3390/cells9020506

Cited by 83 publications

(73 citation statements)

References 199 publications

(234 reference statements)

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“…But research over the last several decades demonstrates additional models of GPCR signaling including G-protein coupled receptor kinases (GRKs) and β-arrestins ( 71 , 72 ) and homo- and hetero-dimerization of monomeric GPCR molecules ( 73 , 74 ). Despite the structural and general function commonality of GPCRs, individual GPCRs are extremely functionally diverse given the wide variety of ligands and stimuli they respond to, including but not limited to: biogenic amines, hormones, peptides, cations, lipids, glycoproteins, pheromones, synthetic drugs, tastes, odors, stress, and light ( 75 , 76 ). Therefore, activation of GPCRs can lead to various effects on cellular function, including cell homeostasis, intra- and extracellular signaling, and physiology at a macro level; and initiation/termination of transcription, activation of ion channels and neuronal excitability, and hormone release at a micro level.…”

Section: Systems Communication In Social Attachment: Oxytocinergic Dmentioning

confidence: 99%

Oxytocin, Dopamine, and Opioid Interactions Underlying Pair Bonding: Highlighting a Potential Role for Microglia

Loth

Donaldson

2020

Endocrinology

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Pair bonds represent some of the strongest attachments we form as humans. These relationships positively modulate health and well-being. Conversely, the loss of a spouse is an emotionally painful event that leads to numerous deleterious physiological effects, including increased risk for cardiac dysfunction and mental illness. Much of our understanding of the neuroendocrine basis of pair bonding has come from studies of monogamous prairie voles (Microtus ochrogaster), laboratory-amenable rodents that, unlike laboratory mice and rats, form lifelong pair bonds. Specifically, research using prairie voles has delineated a role for multiple neuromodulatory and neuroendocrine systems in the formation and maintenance of pair bonds, including the oxytocinergic, dopaminergic, and opioidergic systems. However, while these studies have contributed to our understanding of selective attachment, few studies have examined how interactions among these 3 systems may be essential for expression of complex social behaviors, such as pair bonding. Therefore, in this review, we focus on how the social neuropeptide, oxytocin, interacts with classical reward system modulators, including dopamine and endogenous opioids, during bond formation and maintenance. We argue that an understanding of these interactions has important clinical implications and is required to understand the evolution and encoding of complex social behaviors more generally. Finally, we provide a brief consideration of future directions, including a discussion of the possible roles that glia, specifically microglia, may have in modulating social behavior by acting as a functional regulator of these 3 neuromodulatory systems.

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Section: Systems Communication In Social Attachment: Oxytocinergic Dmentioning

confidence: 99%

Oxytocin, Dopamine, and Opioid Interactions Underlying Pair Bonding: Highlighting a Potential Role for Microglia

Loth

Donaldson

2020

Endocrinology

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“…This condition may facilitate the binding of endogenous ligands and agonists to 5-HT 1A receptors (May et al, 2007;Saleh et al, 2018). Indeed, the allosteric condition of CBD may represent a novel therapeutic strategy to influence the effects of 5-HT 1A receptors (Azam et al, 2020). Radioligand binding assay revealed differences in IC 50 of CBD between hippocampus and temporal neocortex.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol Acts at 5-HT1A Receptors in the Human Brain: Relevance for Treating Temporal Lobe Epilepsy

Martínez-Aguirre¹,

Carmona-Cruz²,

Velasco

et al. 2020

Front. Behav. Neurosci.

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Experimental evidence indicates that cannabidiol (CBD) induces anxiolytic and antiepileptic effects through the activation of 5-HT1A receptors. These receptors are coupled to Gi/o proteins and induce inhibitory effects. At present, the interaction of CBD with 5-HT1A receptors in the human brain is unknown. The aim of this study focused on evaluating the interaction between CBD and 5-HT1A receptors in cell membranes obtained from the hippocampus and temporal neocortex of autopsies and patients with drug-resistant mesial temporal lobe epilepsy (DR-MTLE). Cell membranes were isolated from the hippocampus and temporal neocortex of a group of patients with DR-MTLE who were submitted to epilepsy surgery (n = 11) and from a group of autopsies (n = 11). The [3H]-8-OH-DPAT binding assay was used to determine the pharmacological interaction of CBD with 5-HT1A receptors. The [35S]-GTPγS assay was used to investigate the CBD-induced activation of Gi/o proteins through its action on 5-HT1A receptors.The CBD affinity (pKi) for 5-HT1A receptors was similar for autopsies and patients with DR-MTLE (hippocampus: 4.29 and 4.47, respectively; temporal neocortex: 4.67 and 4.74, respectively). Concerning the [35S]-GTPγS assay, no statistically significant changes were observed for both hippocampal and neocortical tissue (p > 0.05) at low CBD concentrations (1 pM to 10 μM). In contrast, at high concentrations (100 μM), CBD reduced the constitutive activity of Gi/o proteins of autopsies and DR-MTLE patients (hippocampus: 39.2% and 39.6%, respectively; temporal neocortex: 35.2% and 24.4%, respectively). These changes were partially reversed in the presence of WAY-100635, an antagonist of 5-HT1A receptors, in the autopsy group (hippocampus, 59.8%, p < 0.0001; temporal neocortex, 71.5%, p < 0.0001) and the group of patients with DR-MTLE (hippocampus, 53.7%, p < 0.0001; temporal neocortex, 68.5%, p < 0.001). Our results show that CBD interacts with human 5-HT1A receptors of the hippocampus and temporal neocortex. At low concentrations, the effect of CBD upon Gi/o protein activation is limited. However, at high concentrations, CBD acts as an inverse agonist of 5-HT1A receptors. This effect could modify neuronal excitation and epileptic seizures in patients with DR-MTLE.

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“…Another study has found that pathway of GPCR was overrepresented and it is associated with pediatric obesity [35]. As a potential therapeutic target for intervention in cognitive deficits, the association of GPCR signaling pathway with BMI could reflect the intrinsic connection between cognition and obesity [36,37]. Table 3 also contains significant pathways directly related to metabolism of lipids, lipoproteins and carbohydrates, etc.…”

Section: Discussionmentioning

confidence: 99%

Global Gene Expression Profiling of Body-Mass Index in Middle-Aged Danish Twins

Baumbach

Mohammadnejad³

et al. 2020

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Objective: The body mass index (BMI) measured as weight in relation to height is an important monitor for obesity and diabetes, with individual variation under control by genetic and environmental factors. In transcriptome-wide association studies on BMI, the genetic contribution calls for controlling of genetic confounding that affects both BMI and gene expression. We performed a global gene expression profiling of BMI on peripheral blood cells using monozygotic twins for efficient handling of genetic make-ups. Methods: We applied a generalized association method to genome-wide gene expression data on 229 pairs of monozygotic twins (age 56-80 years) for detecting diverse patterns of correlation between BMI and gene expression. Results: We detected seven probes associated with BMI with p<1e-04, among them two probes with p<1e05 (p=2.83e-06 AAK1; p=7.83e-06 LILRA3). In total, the analysis found 1579 probes with nominal p<0.05. Biological pathway analysis of enriched pathways found 50 KEGG and 45 Reactome pathways (FDR<0.05). The identified top functional pathways included immune function, JAK-STAT signalling, insulin signalling and regulation of energy metabolism. Conclusion: This transcriptome-wide association study using monozygotic twins and generalized correlation identified differentially expressed genes and a broad spectrum of enriched biological pathways that may implicate metabolic health.

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G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

Cited by 83 publications

References 199 publications

Oxytocin, Dopamine, and Opioid Interactions Underlying Pair Bonding: Highlighting a Potential Role for Microglia

Oxytocin, Dopamine, and Opioid Interactions Underlying Pair Bonding: Highlighting a Potential Role for Microglia

Cannabidiol Acts at 5-HT1A Receptors in the Human Brain: Relevance for Treating Temporal Lobe Epilepsy

Global Gene Expression Profiling of Body-Mass Index in Middle-Aged Danish Twins

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