Nil Casajuana‐Martin

Universitat Autònoma de Barcelona

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Leonardo Pardo

Universitat Autònoma de Barcelona

Sergi Ferré

National Institute on Drug Abuse

Vicent Casadó

Universitat de Barcelona

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Ángel González

Universitat Autònoma de Barcelona

Claudia Llinás del Torrent

Universitat Autònoma de Barcelona

Verònica Casadó-Anguera

Universitat de Barcelona

Estefanía Moreno

Universitat de Barcelona

Natàlia Llopart

Universitat de Barcelona

David Weinshenker

Emory University

Gemma Navarro

Instituto de Salud Carlos III

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Universitat de Barcelona

National Institute on Drug Abuse

Universitat Autònoma de Barcelona

National Institutes of Health

Institut de Biomedicina de la Universitat de Barcelona

Institut d'Investigació Biomédica de Bellvitge

Bellvitge University Hospital

Biomedical Research Networking Center on Neurodegenerative Diseases

Instituto de Salud Carlos III

Centro de Investigación Biomédica en Red

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Additional file 4 of The mutational landscape of human olfactory G protein-coupled receptors

Figshare (2021)

Ramón Cierco Jimenez Nil Casajuana‐Martin Adrián García‐Recio Lidia Alcántara Leonardo Pardo

Additional file 4. The human OR mutation database table. The mutation data table is available at the human Olfactory Receptor Mutation database (hORMdb) website and contains information of 119,069 natural human OR nucleotide variants extracted from gnomAD v2 and annotated with genomic and structural information as described in the main text (resumed in the diagram of Fig. 1). A total of 78 descriptors were associated with each of the natural variants generating a total of 9,287,382 data points. More information about the data types at each column can be found at the HELP panel on the hORMdb web application.

10.6084/m9.figshare.13725081

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Pharmacological targeting of G protein-coupled receptor heteromers

Pharmacological Research (2022)

Estefanía Moreno Nil Casajuana‐Martin Michael Coyle Baruc Campos Ewa Galaj

A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D1 and D3 receptors (D1R and D3R) influences the pharmacological properties of three structurally similar selective dopamine D3R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4–116. By using D1R-D3R heteromer-disrupting peptides, it could be demonstrated that the three D3R ligands display different D1R-D3R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D1R-mediated signaling in the D1R-D3R heteromer; PG01037, acting as a D3R antagonist cross-antagonized D1R-mediated signaling in the D1R-D3R heteromer; and VK4–116 specifically acted as a ß-arrestin-biased agonist in the D1R-D3R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D3R ligands that are dependent on D1R-D3R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D3R ligands in vivo. The results supported the involvement of D1R-D3R heteromers in the locomotor activation by D1R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D1R-D3R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinson’s disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.

Functional selectivity

10.1016/j.phrs.2022.106476

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Insights of schizophrenia associated dopamine D2 receptor variants: interplay with the adenosinergic system

Neuroscience Applied (2023)

Francisco Ciruela Marta Valle-León Claudia Llinás del Torrent Paula Álvarez-Montoya Marc López‐Cano

Adenosinergic

10.1016/j.nsa.2023.103686

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The ADORA1 mutation linked to early-onset Parkinson’s disease alters adenosine A1-A2A receptor heteromer formation and function

Biomedicine & Pharmacotherapy (2022)

Laura I. Sarasola Claudia Llinás del Torrent Andrea Pérez Arévalo Josep Argerich Nil Casajuana‐Martin

Adenosine modulates neurotransmission through inhibitory adenosine A1 receptors (A1Rs) and stimulatory A2A receptors (A2ARs). These G protein-coupled receptors are involved in motor function and related to neurodegenerative diseases such as Parkinson's disease (PD). An autosomal-recessive mutation (G2797.44S) within the transmembrane helix (TM) 7 of A1R (A1RG279S) has been associated with the development of early onset PD (EOPD). Here, we aimed at investigating the impact of this mutation on the structure and function of the A1R and the A1R-A2AR heteromer. Our results revealed that the G2797.44S mutation does not alter A1R expression, ligand binding, constitutive activity or coupling to transducer proteins (Gαi, Gαq, Gα12/13, Gαs, β-arrestin2 and GRK2) in transfected HEK-293 T cells. However, A1RG279S weakened the ability of A1R to heteromerize with A2AR, as shown in a NanoBiT assay, which led to the disappearance of the heteromerization-dependent negative allosteric modulation that A1R imposes on the constitutive activity and agonist-induced activation of the A2AR. Molecular dynamic simulations allowed to propose an indirect mechanism by which the G2797.44S mutation in TM 7 of A1R weakens the TM 5/6 interface of the A1R-A2AR heteromer. Therefore, it is demonstrated that a PD linked ADORA1 mutation is associated with dysfunction of adenosine receptor heteromerization. We postulate that a hyperglutamatergic state secondary to increased constitutive activity and sensitivity to adenosine of A2AR not forming heteromers with A1R could represent a main pathogenetic mechanism of the EOPD associated with the G2797.44S ADORA1 mutation.

Adenosine A2A receptor

10.1016/j.biopha.2022.113896

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Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone

Molecular Psychiatry (2023)

Marjorie R. Levinstein Paulo Alexandre de Oliveira Nil Casajuana‐Martin César Quiroz Reece C. Budinich

Abuse liability

Pharmacodynamics

10.1038/s41380-023-02353-z

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Heterobivalent Ligand for the Adenosine A_2A–Dopamine D₂ Receptor Heteromer

Journal of Medicinal Chemistry (2022)

Daniel Pulido Verònica Casadó-Anguera Marc Gómez‐Autet Natàlia Llopart Estefanía Moreno

A G protein-coupled receptor heteromer that fulfills the established criteria for its existence in vivo is the complex between adenosine A2A (A2AR) and dopamine D2 (D2R) receptors. Here, we have designed and synthesized heterobivalent ligands for the A2AR–D2R heteromer with various spacer lengths. The indispensable simultaneous binding of these ligands to the two different orthosteric sites of the heteromer has been evaluated by radioligand competition-binding assays in the absence and presence of specific peptides that disrupt the formation of the heteromer, label-free dynamic mass redistribution assays in living cells, and molecular dynamic simulations. This combination of techniques has permitted us to identify compound 26 [KDB1 (A2AR) = 2.1 nM, KDB1 (D2R) = 0.13 nM], with a spacer length of 43-atoms, as a true bivalent ligand that simultaneously binds to the two different orthosteric sites. Moreover, bioluminescence resonance energy transfer experiments indicate that 26 favors the stabilization of the A2AR–D2R heteromer.

Adenosine A2A receptor

10.1021/acs.jmedchem.1c01763

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Design of Negative and Positive Allosteric Modulators of the Cannabinoid CB₂ Receptor Derived from the Natural Product Cannabidiol

Journal of Medicinal Chemistry (2021)

Gemma Navarro Ángel González Adrià Sánchez-Morales Nil Casajuana‐Martin Marc Gómez-Ventura

Cannabidiol (CBD), the second most abundant of the active compounds found in the Cannabis sativa plant, is of increasing interest because it is approved for human use and is neither euphorizing nor addictive. Here, we design and synthesize novel compounds taking into account that CBD is both a partial agonist, when it binds to the orthosteric site, and a negative allosteric modulator, when it binds to the allosteric site of the cannabinoid CB2 receptor. Molecular dynamic simulations and site-directed mutagenesis studies have identified the allosteric site near the receptor entrance. This knowledge has permitted to perform structure-guided design of negative and positive allosteric modulators of the CB2 receptor with potential therapeutic utility.

Allosteric modulator

Natural product

10.1021/acs.jmedchem.1c00561

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Citations (35)

Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone

Research Square (Research Square) (2023)

Michael Michaelides Marjorie R. Levinstein Paulo De Oliveira Nil Casajuana‐Martin César Quiroz

Abstract (R,S)-methadone ((R,S)-MTD) is a racemic µ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers used for the treatment of opioid use disorder (OUD) and pain. (R)-MTD is used as an OUD treatment, has high MOR potency, and is believed to mediate (R,S)-MTD’s therapeutic efficacy. (S)-MTD is in clinical development as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. In opposition to this purported mechanism of action, we found that (S)-MTD does not occupy NMDARs in vivo in rats. Instead, (S)-MTD produced MOR occupancy and induced analgesia with similar efficacy as (R)-MTD. Unlike (R)-MTD, (S)-MTD was not self-administered and failed to increase locomotion or extracellular dopamine levels indicating low abuse liability. Moreover, (S)-MTD antagonized the effects of (R)-MTD in vivo and exhibited unique pharmacodynamic properties, distinct from those of (R)-MTD. Specifically, (S)-MTD acted as a MOR partial agonist with a specific loss of efficacy at the MOR-galanin 1 receptor (Gal1R) heteromer, a key mediator of the dopaminergic effects of opioids. In sum, we report novel and unique pharmacodynamic properties of (S)-MTD that are relevant to its potential mechanism of action and therapeutic use, as well as those of (R,S)-MTD.

Pharmacodynamics

10.21203/rs.3.rs-2644719/v1

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Citations (1)

Molecular basis for the therapeutic use of methadone

Neuroscience Applied (2023)

Verònica Casadó-Anguera Natàlia Llopart A. Alonso-Carrasco Ning-Sheng Cai Nil Casajuana‐Martin

Basis (linear algebra)

10.1016/j.nsa.2023.102714

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The mutational landscape of human olfactory G protein-coupled receptors

BMC Biology (2021)

Ramón Cierco Jimenez Nil Casajuana‐Martin Adrián García‐Recio Lidia Alcántara Leonardo Pardo

Abstract Background Olfactory receptors (ORs) constitute a large family of sensory proteins that enable us to recognize a wide range of chemical volatiles in the environment. By contrast to the extensive information about human olfactory thresholds for thousands of odorants, studies of the genetic influence on olfaction are limited to a few examples. To annotate on a broad scale the impact of mutations at the structural level, here we analyzed a compendium of 119,069 natural variants in human ORs collected from the public domain. Results OR mutations were categorized depending on their genomic and protein contexts, as well as their frequency of occurrence in several human populations. Functional interpretation of the natural changes was estimated from the increasing knowledge of the structure and function of the G protein-coupled receptor (GPCR) family, to which ORs belong. Our analysis reveals an extraordinary diversity of natural variations in the olfactory gene repertoire between individuals and populations, with a significant number of changes occurring at the structurally conserved regions. A particular attention is paid to mutations in positions linked to the conserved GPCR activation mechanism that could imply phenotypic variation in the olfactory perception. An interactive web application (hORMdb, Human Olfactory Receptor Mutation Database) was developed for the management and visualization of this mutational dataset. Conclusion We performed topological annotations and population analysis of natural variants of human olfactory receptors and provide an interactive application to explore human OR mutation data. We envisage that the utility of this information will increase as the amount of available pharmacological data for these receptors grow. This effort, together with ongoing research in the study of genetic changes in other sensory receptors could shape an emerging sensegenomics field of knowledge, which should be considered by food and cosmetic consumer product manufacturers for the benefit of the general population.

10.1186/s12915-021-00962-0

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Citations (24)