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Function of Neurotransmitter Receptors in Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 12208

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Special Issue Editors

Dr. Xavier Altafaj

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Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Campus Clínic, IDIBAPS, Universitat de Barcelona, c/ Casanova 143, 08036 Barcelona, Spain
Interests: NMDA receptors; glutamatergic synapse; neurodevelopmental disorders; precision medicine

Prof. Dr. Francisco Ciruela

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Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, Campus Bellvitge, IDIBELL, Universitat de Barcelona. Av. Feixa Llarga, s/n, 08907 L’Hospitalet de Llobregat, Spain
Interests: G protein-coupled receptors; adenosine receptors; neuropharmacology; neurological diseases; allosteric modulation; receptor-receptor interactions; psychiatric diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurotransmitter receptors are membrane proteins of excitable cells responsible for the transduction of chemical signals (e.g., neurotransmitters, neurohormones) into ion- and/or second messengers-mediated signaling cascades, namely ionotropic and metabotropic neurotransmitter receptors, respectively. Thus, while metabotropic receptors are coupled to G proteins (i.e. GPCRs, G protein-coupled receptors), ionotropic receptors are in fact ligand-gated ion channels. Concomitantly with their pivotal role in neuronal physiology, neuropathological conditions are often a result of either primary or secondary alterations of neurotransmitter receptor dysfunctions. Many neurodevelopmental, neuropsychiatric, and neurodegenerative disorders are strongly associated with neurotransmitter receptors activity disturbance. Accordingly, neurotransmitter receptor activity both in health and disease is a hot research topic in molecular, structural, and pharmacological neurology. In recent years, the study of neurotransmitter receptors has emerged, as a result of the integration of a growing number of structural data (crystal structures of neurotransmitter receptors), genetic data (de novo variants affecting neurotransmitter receptors), and molecular pharmacology. Overall, the mechanistic knowledge of neurotransmitter receptors is expanding, making it possible to define and evaluate precision therapeutic tools for clinical practice.

This Special Issue will provide the reader with a flavor of the investigations focused on neurotransmitter receptors, both from fundamental and clinical angles. Submission of original research manuscripts describing molecular, physiological, neuropathological, and pharmacological advances related to neurotransmitter receptors, are welcome. In addition, manuscripts describing new pharmacological tools/approaches for the study of neurotransmitter receptor function, perspectives on therapeutic approaches for neurotransmitter receptors, and reviews will be also taken into consideration. Finally, authors are encouraged to propose topics that will be evaluated accordingly. Overall, we hope that this issue summarizing the current knowledge of neurotransmitter receptors in health and disease will be of interest to a wide range of readers of the journal.

Dr. Xavier Altafaj
Prof. Dr. Francisco Ciruela
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

neurotransmission
synaptic dysfunction
ion channel receptors
G protein-coupled receptors
agonist
therapeutics
molecular mechanisms
crystal structure
precision medicine
signal transduction
antagonist
receptor-receptor interactions
neurodegeneration
neuropsychiatric diseases
neurodevelopmental disorders

Published Papers (4 papers)

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Research

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19 pages, 4804 KiB

Open AccessArticle

Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum

by Ana Santos-Gómez, Federico Miguez-Cabello, Natalia Juliá-Palacios, Deyanira García-Navas, Víctor Soto-Insuga, Juan J. García-Peñas, Patricia Fuentes, Salvador Ibáñez-Micó, Laura Cuesta, Ramón Cancho, Patricia Andreo-Lillo, Gema Gutiérrez-Aguilar, Olga Alonso-Luengo, Ignacio Málaga, Antonio Hedrera-Fernández, Àngels García-Cazorla, David Soto, Mireia Olivella and Xavier Altafaj

Int. J. Mol. Sci. 2021, 22(23), 12656; https://doi.org/10.3390/ijms222312656 - 23 Nov 2021

Cited by 5 | Viewed by 2334

Abstract

Background: GRIN-related disorders (GRD), the so-called grinpathies, is a group of rare encephalopathies caused by mutations affecting GRIN genes (mostly GRIN1, GRIN2A and GRIN2B genes), which encode for the GluN subunit of the N-methyl D-aspartate (NMDA) type ionotropic glutamate receptors. A growing number of functional studies indicate that GRIN-encoded GluN1 subunit disturbances can be dichotomically classified into gain- and loss-of-function, although intermediate complex scenarios are often present. Methods: In this study, we aimed to delineate the structural and functional alterations of GRIN1 disease-associated variants, and their correlations with clinical symptoms in a Spanish cohort of 15 paediatric encephalopathy patients harbouring these variants. Results: Patients harbouring GRIN1 disease-associated variants have been clinically deeply-phenotyped. Further, using computational and in vitro approaches, we identified different critical checkpoints affecting GluN1 biogenesis (protein stability, subunit assembly and surface trafficking) and/or NMDAR biophysical properties, and their association with GRD clinical symptoms. Conclusions: Our findings show a strong correlation between GRIN1 variants-associated structural and functional outcomes. This structural-functional stratification provides relevant insights of genotype-phenotype association, contributing to future precision medicine of GRIN1-related encephalopathies. Full article

(This article belongs to the Special Issue Function of Neurotransmitter Receptors in Health and Disease)

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20 pages, 4701 KiB

Open AccessArticle

The Density of Group I mGlu₅ Receptors Is Reduced along the Neuronal Surface of Hippocampal Cells in a Mouse Model of Alzheimer’s Disease

by Alejandro Martín-Belmonte, Carolina Aguado, Rocío Alfaro-Ruiz, José Luis Albasanz, Mairena Martín, Ana Esther Moreno-Martínez, Yugo Fukazawa and Rafael Luján

Int. J. Mol. Sci. 2021, 22(11), 5867; https://doi.org/10.3390/ijms22115867 - 30 May 2021

Cited by 8 | Viewed by 2476

Abstract

Metabotropic glutamate receptor subtype 5 (mGlu₅) is implicated in the pathophysiology of Alzheimer’s disease (AD). However, its alteration at the subcellular level in neurons is still unexplored. Here, we provide a quantitative description on the expression and localisation patterns of mGlu₅ in the APP/PS1 model of AD at 12 months of age, combining immunoblots, histoblots and high-resolution immunoelectron microscopic approaches. Immunoblots revealed that the total amount of mGlu₅ protein in the hippocampus, in addition to downstream molecules, i.e., G_q/11 and PLCβ₁, was similar in both APP/PS1 mice and age-matched wild type mice. Histoblots revealed that mGlu₅ expression in the brain and its laminar expression in the hippocampus was also unaltered. However, the ultrastructural techniques of SDS-FRL and pre-embedding immunogold demonstrated that the subcellular localisation of mGlu₅ was significantly reduced along the neuronal surface of hippocampal principal cells, including CA1 pyramidal cells and DG granule cells, in APP/PS1 mice at 12 months of age. The decrease in the surface localisation of mGlu₅ was accompanied by an increase in its frequency at intracellular sites in the two neuronal populations. Together, these data demonstrate, for the first time, a loss of mGlu₅ at the plasma membrane and accumulation at intracellular sites in different principal cells of the hippocampus in APP/PS1 mice, suggesting an alteration of the excitability and synaptic transmission that could contribute to the cognitive dysfunctions in this AD animal model. Further studies are required to elucidate the specificity of mGlu₅-associated molecules and downstream signalling pathways in the progression of the pathology. Full article

(This article belongs to the Special Issue Function of Neurotransmitter Receptors in Health and Disease)

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16 pages, 1603 KiB

Open AccessArticle

Dopamine D₂ Receptor Agonist Binding Kinetics—Role of a Conserved Serine Residue

by Richard Ågren, Tomasz Maciej Stepniewski, Hugo Zeberg, Jana Selent and Kristoffer Sahlholm

Int. J. Mol. Sci. 2021, 22(8), 4078; https://doi.org/10.3390/ijms22084078 - 15 Apr 2021

Cited by 5 | Viewed by 2276

Abstract

The forward (k_on) and reverse (k_off) rate constants of drug–target interactions have important implications for therapeutic efficacy. Hence, time-resolved assays capable of measuring these binding rate constants may be informative to drug discovery efforts. Here, we used an ion channel activation assay to estimate the k_ons and k_offs of four dopamine D₂ receptor (D₂R) agonists; dopamine (DA), p-tyramine, (R)- and (S)-5-OH-dipropylaminotetralin (DPAT). We further probed the role of the conserved serine S193^5.42 by mutagenesis, taking advantage of the preferential interaction of (S)-, but not (R)-5-OH-DPAT with this residue. Results suggested similar k_offs for the two 5-OH-DPAT enantiomers at wild-type (WT) D₂R, both being slower than the k_offs of DA and p-tyramine. Conversely, the k_on of (S)-5-OH-DPAT was estimated to be higher than that of (R)-5-OH-DPAT, in agreement with the higher potency of the (S)-enantiomer. Furthermore, S193^5.42A mutation lowered the k_on of (S)-5-OH-DPAT and reduced the potency difference between the two 5-OH-DPAT enantiomers. Kinetic K_ds derived from the k_off and k_on estimates correlated well with EC₅₀ values for all four compounds across four orders of magnitude, strengthening the notion that our assay captured meaningful information about binding kinetics. The approach presented here may thus prove valuable for characterizing D₂R agonist candidate drugs. Full article

(This article belongs to the Special Issue Function of Neurotransmitter Receptors in Health and Disease)

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Review

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40 pages, 1549 KiB

Open AccessReview

Allosteric Interactions between Adenosine A_2A and Dopamine D₂ Receptors in Heteromeric Complexes: Biochemical and Pharmacological Characteristics, and Opportunities for PET Imaging

by Kavya Prasad, Erik F. J. de Vries, Philip H. Elsinga, Rudi A. J. O. Dierckx and Aren van Waarde

Int. J. Mol. Sci. 2021, 22(4), 1719; https://doi.org/10.3390/ijms22041719 - 09 Feb 2021

Cited by 14 | Viewed by 4055

Abstract

Adenosine and dopamine interact antagonistically in living mammals. These interactions are mediated via adenosine A_2A and dopamine D₂ receptors (R). Stimulation of A_2AR inhibits and blockade of A_2AR enhances D₂R-mediated locomotor activation and goal-directed behavior in rodents. In striatal membrane preparations, adenosine decreases both the affinity and the signal transduction of D₂R via its interaction with A_2AR. Reciprocal A_2AR/D₂R interactions occur mainly in striatopallidal GABAergic medium spiny neurons (MSNs) of the indirect pathway that are involved in motor control, and in striatal astrocytes. In the nucleus accumbens, they also take place in MSNs involved in reward-related behavior. A_2AR and D₂R co-aggregate, co-internalize, and co-desensitize. They are at very close distance in biomembranes and form heteromers. Antagonistic interactions between adenosine and dopamine are (at least partially) caused by allosteric receptor–receptor interactions within A_2AR/D₂R heteromeric complexes. Such interactions may be exploited in novel strategies for the treatment of Parkinson’s disease, schizophrenia, substance abuse, and perhaps also attention deficit-hyperactivity disorder. Little is known about shifting A_2AR/D₂R heteromer/homodimer equilibria in the brain. Positron emission tomography with suitable ligands may provide in vivo information about receptor crosstalk in the living organism. Some experimental approaches, and strategies for the design of novel imaging agents (e.g., heterobivalent ligands) are proposed in this review. Full article

(This article belongs to the Special Issue Function of Neurotransmitter Receptors in Health and Disease)

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