Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

Lara, César O.; Burgos, Carlos F.; Moraga-Cid, Gustavo; Carrasco, Mónica A.; Yévenes, Gonzalo E.

doi:10.3389/fphar.2020.00167

Cited by 10 publications

(6 citation statements)

References 76 publications

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“…In agreement with this concept, a recent study in rats found that diazepam reverted the toxicity induced by gelsenicine, another Gelsemium alkaloid ( Li et al, 2022 ). Further studies on inhibitory receptors may generate a rational framework to design targeted pharmacological approaches to treat acute Gelsemium alkaloid toxicity through, for example, positive allosteric modulators of GlyRs or of GABA A Rs ( Lara et al, 2020 ; Cerne et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Modulation of GABAA receptors and of GABAergic synapses by the natural alkaloid gelsemine

Marileo

Gavilán²,

Martín³

et al. 2023

Front. Mol. Neurosci.

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The Gelsemium elegans plant preparations have shown beneficial activity against common diseases, including chronic pain and anxiety. Nevertheless, their clinical uses are limited by their toxicity. Gelsemine, one of the most abundant alkaloids in the Gelsemium plants, have replicated these therapeutic and toxic actions in experimental behavioral models. However, the molecular targets underlying these biological effects remain unclear. The behavioral activity profile of gelsemine suggests the involvement of GABAA receptors (GABAARs), which are the main biological targets of benzodiazepines (BDZs), a group of drugs with anxiolytic, hypnotic, and analgesic properties. Here, we aim to define the modulation of GABAARs by gelsemine, with a special focus on the subtypes involved in the BDZ actions. The gelsemine actions were determined by electrophysiological recordings of recombinant GABAARs expressed in HEK293 cells, and of native receptors in cortical neurons. Gelsemine inhibited the agonist-evoked currents of recombinant and native receptors. The functional inhibition was not associated with the BDZ binding site. We determined in addition that gelsemine diminished the frequency of GABAergic synaptic events, likely through a presynaptic modulation. Our findings establish gelsemine as a negative modulator of GABAARs and of GABAergic synaptic function. These pharmacological features discard direct anxiolytic or analgesic actions of gelsemine through GABAARs but support a role of GABAARs on the alkaloid induced toxicity. On the other hand, the presynaptic effects of the alkaloid provide an additional mechanism to explain their beneficial effects. Collectively, our results contribute novel information to improve understanding of gelsemine actions in the mammalian nervous system.

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Section: Discussionmentioning

confidence: 99%

Modulation of GABAA receptors and of GABAergic synapses by the natural alkaloid gelsemine

Marileo

Gavilán²,

Martín³

et al. 2023

Front. Mol. Neurosci.

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“…We performed molecular docking assays using the structures available for GlyRs and GABA A Rs to start the molecular examination of the alkaloid’s interaction with these ion channels [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Due to their relevance as the structural domains responsible for binding agonists, antagonists, and allosteric modulators [ 24 ], the docking procedures focused on the extracellular domain (ECD) and transmembrane domains (TMD). Our bioinformatic assays revealed that a major percentage of the alkaloid–GlyR (≈81–95%) and alkaloid–GABA A R (≈74%) complexes were located on the receptor ECD, while few interactions were positioned on the TMDs ( Figure S1 ).…”

Section: Resultsmentioning

confidence: 99%

Molecular Pharmacology of Gelsemium Alkaloids on Inhibitory Receptors

Marileo,

Lara,

Sazo

et al. 2024

IJMS

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Indole alkaloids are the main bioactive molecules of the Gelsemium genus plants. Diverse reports have shown the beneficial actions of Gelsemium alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, Gelsemium alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of Gelsemium alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABAA receptors (GABAARs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between Gelsemium alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC50 of 31.5 ± 1.7 and 40.6 ± 8.2 μM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABAARs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major Gelsemium indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS.

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“…Hydroxychloroquine was also active on modulating ion channel receptors (bioactivity : 0.30). Ligand-dependent ion channels are also pharmacological targets for the development of new therapies 36 . For receptors of kinase inhibitors, the bioactivity of hydroxychloroquine is 0.44).…”

Section: Prediction Of Bioactivitymentioning

confidence: 99%

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2021

IJPSR

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Hydroxychloroquine, widely used to treat certain autoimmune diseases and inflammatory conditions, has been repositioned as a new lead against the COVID-19 pandemic. Preliminary studies have suggested that hydroxychloroquine inhibits the entry of the SARS-CoV2 virus mediated by the ACE2 receptor and is a particularly interesting anti-inflammatory and immunomodulatory action in the cytokine storm during COVID-19 infection. Furthermore, cardiovascular effects have been reported in hypertensive patients. These last are thought to result from the inhibition of cyclooxygenase 2. Our results reveal for the first time in atomic detail how hydroxychloroquine, one of the most controversial drugs, has an affinity for a new molecular target (COX2) with a docking score: -7.6 (kcal/mol) and a root mean square deviation (RMSD = 2.542). Hydroxychloroquine binds to cyclo-oxygenase 2 via two hydrogen bonds (H-GLY136 and H-GLY45) and four hydrophobic bonds: Cl -CYS36, 0 -CYS36, 0 -CYS47 and 0 -PRO154). This mechanism has never been elucidated. Hydroxychloroquine proved to be promiscuous. Its structure, which differs from that of non-steroidal anti-inflammatory drugs , tends to show activity against a wide variety of biological targets : As an enzyme inhibitor (bioactivity = 0.15), GPCR receptor ligand (bioactivity = 0.35), ion channel modulator (bioactivity = 0.30), kinase inhibitor (bioactivity = 0.44) and protease inhibitor (bioactivity = 0.12). This approach improves the understanding of its mechanism of action and the side effects attributed to it. INTRODUCTION:While the main scientific research has focused on chronic non-communicable diseases in recent decades. The year 2019-2020 was marked by the emergence of a new COVID-19 epidemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1, 2 . This pandemic has challenged health systems around the world 3 .

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Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

Cited by 10 publications

References 76 publications

Modulation of GABAA receptors and of GABAergic synapses by the natural alkaloid gelsemine

Modulation of GABAA receptors and of GABAergic synapses by the natural alkaloid gelsemine

Molecular Pharmacology of Gelsemium Alkaloids on Inhibitory Receptors

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