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Architecture of Cys-loop receptors. Structure of (left) Torpedo nAChR solved from electron microscopic images at the 4 A ˚ level ( pdb 2BG9) (Unwin 2005) and (right) the C. elegans glutamate-gated anion channel at 3.3 A ˚ ( pdb 3RIA) (Hibbs and Gouaux 2011). The pentameric subunit assembly and secondary structure are shown for the extracellular domain (ECD) and transmembrane domain (TMD). The ECDs are composed of inner and outer b-sheets with an a-helix, and each subunit's TMD is formed by four a-helices (M1-M4). Note that for nAChR, the intracellular (MA) helices preceding M4 are omitted, whereas the M3-MA stretch is disordered and is thus not included in the structure. For the GluCl structure, the M3-M4 domain is replaced by a tripeptide, A-G-T (Hibbs and Gouaux 2011).
Source publication
Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin...
Contexts in source publication
Context 1
... provided high-resolution images down to 4 A ˚ . These reveal a modular design for nAChRs comprising pseudosymmetrical rings of five subunits, each contributing an extracellular domain (ECD) of anti-parallel sets of inner and outer b-sheets, a four-a-helical transmembrane domain (TMD), and an intracellular domain (ICD) of largely unknown structure (Fig. 1). The ECDs are po- sitioned over the TMDs, providing a central aqueous pathway that stretches from the ex- ternal vestibule formed by the ECDs, on through the TMDs and channel gate, before dis- sipating via the ICDs (Fig. 1). The signature Cys-loop structure is formed by a disulfide bond and contains 13 amino acids situated at the base ...
Context 2
... outer b-sheets, a four-a-helical transmembrane domain (TMD), and an intracellular domain (ICD) of largely unknown structure (Fig. 1). The ECDs are po- sitioned over the TMDs, providing a central aqueous pathway that stretches from the ex- ternal vestibule formed by the ECDs, on through the TMDs and channel gate, before dis- sipating via the ICDs (Fig. 1). The signature Cys-loop structure is formed by a disulfide bond and contains 13 amino acids situated at the base of the ECDs. It is an important conduit for communication between the neurotrans- mitter-binding sites and the ion channel. This overall structure of the receptor agrees reason- ably well with the first crystal structure of ...
Context 3
... amino acids situated at the base of the ECDs. It is an important conduit for communication between the neurotrans- mitter-binding sites and the ion channel. This overall structure of the receptor agrees reason- ably well with the first crystal structure of a Cys-loop receptor, the glutamate-gated Cl 2 channel (GluCl) from Caenorhabditis elegans ( Fig. 1) (Hibbs and Gouaux 2011). This recep- tor also contains a large ECD, four TMDs, and a Cys-loop, in addition to another Cys bridge in loop C, a feature also present in GlyR a-sub- units, with which GluCl shares 43% primary sequence ...
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Ionotropic glutamate receptors (iGluRs) are a major class of ligand‐gated ion channels that are widespread in the living kingdom. Their critical role in excitatory neurotransmission and brain function of arthropods and vertebrates has made them a compelling subject of interest for neurophysiologists and pharmacologists. This is particularly true fo...
Citations
... Neurons rapidly signal to each other via chemical synapses, where neurotransmitter released by one cell diffuses across a narrow synaptic cleft and binds to ligand-gated ion channels (LGICs), or ''ionotropic receptors,'' on the postsynaptic cell membrane. 1,2 LGICs are membrane proteins with extracellular ligand-binding domains (LBDs) and a membrane-spanning channel domain. Ligand binding in the LBD triggers conformational changes that open (i.e., ''gate'') the channel within milliseconds, mediating rapid ion flux across the cell membrane. ...
... Recent studies have revealed that neurons communicating with each other require a fundamental understanding of neurotransmitter receptor structure and function [31]. In a unified assumption that the cortical neuronal network is sustained in an E-I balanced state, network interactions can suffer much variability due to the difference in fast and slow-acting synapses. ...
Recent experimental observations have supported the hypothesis that the cerebral cortex operates in a dynamical regime near criticality, where the neuronal network exhibits a mixture of ordered and disordered patterns. However, A comprehensive study of how criticality emerges and how to reproduce it is still lacking. In this study, we investigate coupled networks with conductance-based neurons and illustrate the co-existence of different spiking patterns, including asynchronous irregular (AI) firing and synchronous regular (SR) state, along with a scale-invariant neuronal avalanche phenomenon (criticality). We show that fast-acting synaptic coupling can evoke neuronal avalanches in the mean-dominated regime but has little effect in the fluctuation-dominated regime. In a narrow region of parameter space, the network exhibits avalanche dynamics with power-law avalanche size and duration distributions. We conclude that three stages which may be responsible for reproducing the synchronized bursting: mean-dominated subthreshold dynamics, fast-initiating a spike event, and time-delayed inhibitory cancellation. Remarkably, we illustrate the mechanisms underlying critical avalanches in the presence of noise, which can be explained as a stochastic crossing state around the Hopf bifurcation under the mean-dominated regime. Moreover, we apply the ensemble Kalman filter to determine and track effective connections for the neuronal network. The method is validated on noisy synthetic BOLD signals and could exactly reproduce the corresponding critical network activity. Our results provide a special perspective to understand and model the criticality, which can be useful for large-scale modeling and computation of brain dynamics.
... Metabotropic receptors, on the other hand, are connected to ion channels in an indirect manner. Upon binding to a metabotropic receptor, a neurotransmitter triggers a cascade of intracellular second messenger systems, resulting in extensive physiological effects (13). This receptor subtype is implicated with delayed, enduring effects such as the control of gene expression and the adaptability of neurons. ...
Neuro-WiFi, as a non-physical connection-related neural network that efficiently links various regions of the brain, facilitates swift transfer of information and fostering communication among neurons. It is a significant advancement in neuroscience, providing valuable understanding of the intricate connections between neurons and opening up possibilities for precise interventions. This unique neural connection entails the transfer of information between remote parts of the brain via a network resembling WiFi signal. Neuro-WiFi has the potential to greatly enhance our understanding of how information is processed and sent in the brain by facilitating fast and accurate communication over long distances. Envision the ability to modify the neuro-WiFi network to enhance cognitive performance or restore impaired neural circuits. Furthermore, this neuronal connection could have substantial ramifications for the development of therapeutic approaches to address neurological conditions like Alzheimer’s disease or epilepsy. Despite the remaining knowledge gaps around this remarkable phenomenon, through additional investigations, we believe that the mysteries of neuro-WiFi would be extensively uncovered and precise therapies that could profoundly transform our comprehension of brain function and enhance patient outcomes would be provided in the future.
... Glutamate is the major neurotransmitter interacting with both ionotropic and metabotropic receptors for neural excitation by the permeability of ionotropic glutamate receptors to cations [9]. As the main excitatory neurotransmitter, glutamate plays a role in learning, memory, and the production of GABA, an inhibitory neurotransmitter. ...
... The mechanism of communication between synapses depends on the type of synapse. At electrical synapses, gap junctions are intercellular channels that put adjacent cell cytoplasms in direct connection, while chemical synapses release neurotransmitters to carry information from one cell to another [9]. ...
... Neurotransmitters can attach to these cells' receptors to cause cellular changes. After being released, the neurotransmitter travels across the synaptic gap and binds to the receptor site on the other neuron, depending on the neurotransmitter, either stimulating or inhibiting the receiving neuron [9]. The classic synaptic transmission at synapses and diffuse neuromodulator release, which mediates volume transmission, are two examples of neurotransmitter-mediated communication between neurons. ...
... Neurons rapidly signal to each other via chemical synapses, where neurotransmitter released by one cell diffuses across a narrow synaptic cleft and binds to ligand-gated ion channels (LGICs), or "ionotropic receptors", on the postsynaptic cell membrane (1,2). ...
Neurotransmitter ligands electrically excite neurons by activating ionotropic glutamate receptor (iGluR) ion channels. Knowledge of the iGluR amino acid residues that dominate ligand-induced activation would enable the prediction of function from sequence. We therefore explored determinants of activity in rat NMDA-type iGluRs (NMDA receptors), complex heteromeric iGluRs comprising two glycine-binding GluN1 and two glutamate-binding GluN2 subunits, using amino acid sequence analysis, mutagenesis, and electrophysiology. We find that a broadly conserved aspartate residue controls both ligand potency and channel activity, to the extent that certain substitutions at this position bypass the need for ligand-binding in GluN1 subunits, generating NMDA receptors activated solely by glutamate. Furthermore, we identify a homomeric iGluR from the placozoan Trichoplax adhaerens that has utilized this crucial residue to evolve into a leak channel that is inhibited by neurotransmitter binding, pointing to a dominant role of this residue throughout the iGluR superfamily.
... LTM formation is based on the RNA-dependent protein synthesis mechanism and is initiated by releasing neurotransmitters from the presynaptic neuron into the synaptic cleft. Released neurotransmitters may bind with their respective receptors present on the surface of postsynaptic neurons at the synaptic cleft (Davis and Squire 1984;Schafe and LeDoux 2000;Jones et al. 2001;Scharf et al. 2002;Abraham and Robins 2005;Igaz et al. 2006;Fonseca et al. 2006;Abraham and Williams 2008;Alberini 2008;Alberini 2009;Smart and Paoletti 2012;Evans et al. 2021;Lin et al. 2021). As a result of binding of neurotransmitters with the specific postsynaptic membrane receptors may result in the upregulation of cyclic adenosine monophosphate (cAMP). ...
Synaptic plasticity is a result of changes in the neuronal circuits which may result in the formation of protein-dependent (long-term memory (LTM) formation) and protein-independent (short-term memory (STM) formation) memories. This STM formation is based on existing proteins, but LTM formation depends on RNA and protein synthesis within the neuronal cells. This RNA and protein synthesis may depend on stimulus exposure like odour, taste, and other environmental stimuli. The present study is aimed to show the impact of oral bacterial infusions on cognitive memory formation through pre and post-infusive behavioural analysis. The results of the study revealed that oral infusions of Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus and Escherichia coli result in impaired cognitive learning and memory formation. This impaired cognitive memory formation is shown with the help of two-step (pre and post-infusive) behavioural analysis. Pre-infusive behavioural study shows no decline in cognitive learning and memory formation before oral microbial infusions in a serene habituated environment. After oral microbial infusions, a post-infusive behavioural analysis may reveal a memory decline in the treated group. Comparative two-step behavioural analysis indicates that P. aeruginosa infusions strongly impact cognitive memory decline compared to the other three groups. This cognitive memory decline may happen due to the production of primary/secondary metabolites within the animal gut and their transportation to the CNS through the blood-brain barrier. The outcome of the present study states that poor oral hygiene plays a significant role in cognitive memory decline concerning mild cognitive impairment (MCI).
... Although GABAARs, glycine receptors, nACh receptors, and type 3 serotonin (5-HT3) receptors are categorized as pentameric ligand-gated ion channels (pLGICs), general anesthetics generally conduct chloride ions into cells to reduce neuronal excitability in GABAA and glycine receptors but conduct cations in nACh and 5-HT3 receptors (Smart and Paoletti, 2012;Fourati et al., 2018). Moreover, in spinal motor neurons, although inhibitory glycine receptors are always stimulated by the general anesthetics, resulting in the suppression of both postsynaptic N-methyl-D-aspartate (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptors, GABAAR responses can vary among specific channel subtypes or drugs (Cheng and Kendig, 2000). ...
Background
Although the GABAA receptor (GABAAR) has been proposed as the main action site for sevoflurane, isoflurane, halothane, enflurane, propofol, and benzodiazepines (BZDs), binding of these anesthetics with high-resolution structures of the GABAAR have been rarely examined by comparative docking analyses. Moreover, various combinations of ligands on more GABAARs with various subtypes need to be analyzed to understand the elaborate action mechanism of GABAARs better because some GABAA ligands showed specificity toward the distinct subtypes of the GABAAR.
Methods
We performed in silico docking analysis to compare the binding modes of sevoflurane, isoflurane, halothane, enflurane, propofol, and BZDs to the GABAAR based on one of the most recently provided 3D structures. We performed the docking analysis and the affinity-based ranking of the binding sites.
Results
Our docking studies revealed that isoflurane, halothane, and enflurane docked in an extracellular domain (ECD) on GABAARs, in contrast to sevoflurane.
Conclusion
Our results supported a multi-site mechanism for the allosteric modulation of propofol. Propofol was bound to the pore or favored various subsites in the transmembrane domain (TMD). Our result confirmed that different chemically related BZD ligands interact via distinct binding modes rather than by using a common binding mode, as previously suggested.
... Neurotransmitter-gated ion channels constitute a very important group of transmembrane receptor-ion channel complexes in vertebrates and invertebrates. These receptors open transiently upon binding of specific ligands and govern synaptic neurotransmissions in the nervous system and neuromuscular transmissions [52]. Overall, our findings are not surprising, since they exactly match the insecticidal mode of action of the neonicotinoids [53]. ...
The fight against alien invasive insect pests of plants in the urban environment often affects varied sectors of the economy, landscape gardening, public health, and ecology. This paper focuses on the evolution of the red palm weevil in San Benedetto del Tronto, a coastal urban area in central Italy. We investigated the evolution of this insect pest of palm trees in the 2013–2020 period, considering both the effectiveness of the chemicals used and their potentially harmful effects. With a multidisciplinary approach, we carried out a spatio-temporal analysis of the extent and mode of pest spread over time using historical aerial photos, freely available remote sensing images, and field surveys integrated in a GIS environment. We also assessed the toxicity risk associated with the chemicals used to protect the palms from the red weevil. The fight against this weevil is now concentrated in specific areas such as parks, roads, villas, hotels, farmhouses, and nurseries. The preventive chemical treatments applied are very effective in preserving the palms, but they show a toxic potential for all organisms. We discuss current local management of this pest, focusing on several aspects involved in the fight against this beetle in an urban area.
... Together with GABA, the amino acid glycine mediates the bulk of fast inhibitory transmission in the adult CNS [2,97]. Glycine acts by binding to inhibitory GlyRs, which belong to the superfamily of pentameric neurotransmitter receptors (comprising GABA A receptors and nicotinic receptors) and exist as multiple subtypes that differ in their subunit composition [2,[97][98][99]. ...
... Together with GABA, the amino acid glycine mediates the bulk of fast inhibitory transmission in the adult CNS [2,97]. Glycine acts by binding to inhibitory GlyRs, which belong to the superfamily of pentameric neurotransmitter receptors (comprising GABA A receptors and nicotinic receptors) and exist as multiple subtypes that differ in their subunit composition [2,[97][98][99]. GlyRs form glycine-gated ion channels permeable to chloride ions and other anions. ...
GluN3A is a glycine-binding subunit belonging to the NMDA receptor (NMDAR) family that can assemble with GluN1 subunits to form unconventional NMDARs insensitive to glutamate and activated by glycine only. The existence of such excitatory glycine receptors (eGlyRs) in the central nervous system (CNS) has long remained elusive. Recently, eGlyRs have been identified in specific brain regions, where they represent a novel neuronal signaling modality by which extracellular glycine tunes neuronal excitability, circuit function, and behavior. In this review, we summarize the emerging knowledge regarding these underappreciated receptors. The existence of eGlyRs reshapes current understanding of NMDAR diversity and of glycinergic signaling, previously thought to be primarily inhibitory. Given that GluN3A expression is concentrated in brain regions regulating emotional responses, eGlyRs are potential new targets of therapeutic interest in neuropsychiatry.
... Neurotransmitter-gated ion channels constitute a very important group of transmembrane receptor-ion channel complexes in vertebrates and invertebrates. These receptors open transiently upon binding of specific ligands and govern synaptic neurotransmissions in the nervous system and neuromuscular transmissions [52]. Overall, our findings are not surprising, since they exactly match the insecticidal mode of action of the neonicotinoids [53]. ...
The implications related to the fight against alien organisms often affect different sectors, from the economic to the landscape one or from the public health to the ecological one. This paper is an upgrade of our previous study focused on the evolution of the red palm weevil in a coastal urban area (central Italy); we investigate the evolution of this parasite in the following period (2013-2020), considering both the effectiveness of the chemicals used and their potential effects. With a multidisciplinary approach, on the one hand we carried out a spatio-temporal analysis to analyze the extent and mode of pest spread over time using historical aerial photos, freely available remote sensing images and field surveys, integrated in a GIS environment, and on the other hand we performed an assessment of the chemical risk associated with the substances used to protect the palms from the red weevil. The fight against weevil is now concentrated in specific areas (parks, relevant roads, villas, hotels, farmhouses, nurseries); the applied preventive chemical treatments are very effective in preserving the palms, but they show a toxic potential for all organisms. We discuss current local management of this pest focusing on the several aspects involve into the fight against this beetle in an urban area.
