Functional modulation of glycine receptors by the alkaloid gelsemine

Lara, César O.; Murath, Pablo; Muñoz, Braulio; Marileo, Ana M.; Martín, Loreto San; Martín, Victoria P. San; Burgos, Carlos F.; Mariqueo, Trinidad; Aguayo, Luis G.; Fuentealba, Jorge; Godoy, Patrício; Guzmán, Leonardo; Yévenes, Gonzalo E.

doi:10.1111/bph.13507

Cited by 39 publications

(51 citation statements)

References 61 publications

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“…In order to explore the impact of the activation of PKA signaling pathway on the elementary ion channel properties, we next performed single-channel recordings of α3GlyRs. In cells co-expressing bPAC and α3GlyRs, in the absence of light, the activation of α3GlyRs resulted in single-channel currents with an average amplitude of 5.47 ± 0.13 pA at +60 mV, as previously shown 27,32,33 . The single-channel amplitudes were stable during 12 minutes of recordings (P = 0.63, paired t-test) ( Fig.…”

Section: Resultssupporting

confidence: 77%

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Modulation of glycine receptor single-channel conductance by intracellular phosphorylation

Moraga-Cid

Martín

Lara

et al. 2020

Sci Rep

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Glycine receptors (GlyRs) are anion-permeable pentameric ligand-gated ion channels (pLGICs). The GlyR activation is critical for the control of key neurophysiological functions, such as motor coordination, respiratory control, muscle tone and pain processing. The relevance of the GlyR function is further highlighted by the presence of abnormal glycinergic inhibition in many pathophysiological states, such as hyperekplexia, epilepsy, autism and chronic pain. In this context, previous studies have shown that the functional inhibition of GlyRs containing the α3 subunit is a pivotal mechanism of pain hypersensitivity. This pathway involves the activation of EP2 receptors and the subsequent PKAdependent phosphorylation of α3GlyRs within the intracellular domain (ICD), which decrease the GlyR-associated currents and enhance neuronal excitability. Despite the importance of this mechanism of glycinergic dis-inhibition associated with dysfunctional α3GlyRs, our current understanding of the molecular events involved is limited. Here, we report that the activation of PKA signaling pathway decreases the unitary conductance of α3GlyRs. We show in addition that the substitution of the PKAtargeted serine with a negatively charged residue within the ICD of α3GlyRs and of chimeric receptors combining bacterial GLic and α3GlyR was sufficient to generate receptors with reduced conductance. Thus, our findings reveal a potential biophysical mechanism of glycinergic dis-inhibition and suggest that post-translational modifications of the ICD, such as phosphorylation, may shape the conductance of other pLGICs. Glycine receptors (GlyRs) belong to the pentameric ligand-gated ion channel (pLGIC) family. GlyRs are anion-permeable channels, allowing the fast influx of chloride and the control of neuronal excitability. An individual GlyR subunit is composed by an extracellular domain (ECD), four transmembrane domains (TM1-4) and an intracellular domain between the TM3 and TM4 domains (ICD) 1-4. To date, a single β subunit and four α subunits (α1-4) has been described. The α subunits share a high degree of sequence identity (≈75%). Nevertheless, they exhibit important differences in their biophysical and pharmacological properties as well as in their distribution along the CNS 1,3,4. In the mammalian CNS, GlyR activity critically controls neurophysiological functions such as motor coordination, respiratory control, muscle tone, as well as pain processing 2,3,5-13. The importance of glycinergic inhibition was first recognized in studies using the GlyR antagonist strychnine 14,15. Later, genetic studies found that mutations in the GlyR α1 and β genes are linked to hyperekplexia in humans 16. More recent evidence has shown that specific GlyR subunits may play key roles in several diseases. For example, while the α1 subunit has been linked to tumorigenesis and alcohol intoxication 17,18 , mutations in the α2 subunit have been linked to autism 19. Alterations in the RNA processing of α3 subunits generates hyperactive receptors, which have been rela...

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Section: Resultssupporting

confidence: 77%

“…The stock solutions of PGE2 were prepared in DMSO and kept at −20 °C. Single channel recordings were performed as previously reported 32,33,42 . The recordings were performed in the cell-attached configuration (+60 mV).…”

Section: Electrophysiologymentioning

confidence: 99%

Modulation of glycine receptor single-channel conductance by intracellular phosphorylation

Moraga-Cid

Martín

Lara

et al. 2020

Sci Rep

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“…The various classes of flavonoids differ in the level of oxidation and the pattern of substitution of the C ring, whereas individual compounds within a class differ in the pattern of substitution of the A and B rings (11). Flavonoids (41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55) in TCM play an important role in analgesia, and have high application value and prospect.…”

Section: Flavonoidsmentioning

confidence: 99%

“…The analgesic action of gelsemine in neuropathic pain was prevented by gene ablation of the GlyR α3 subunitnearly and completely, but not GlyR α1, indicating that gelsemine generates analgesic effect via spinal α3 glycine receptors. Gelsemine directly regulates recombinant and native glycine receptors and play conformational specificity and subunit selectivity effects (53).…”

Section: Regulate Ion Channelsmentioning

confidence: 99%

Progress on Active Analgesic Components and Mechanisms of Commonly Used Traditional Chinese Medicines: A Comprehensive Review

et al. 2018

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Many clinical diseases are accompanied by the symptoms of pain, and the degree of pain is closely related to the patients’ suffering. Therefore, effectively relieving pain has become one of the vital concerns of clinical treatment and analgesic drug research. Non-opioid drugs are mainly used for the clinical treatment of mild to moderate pain, whereas opioid drugs are mainly used for treating moderate to severe pain. However, opioid drugs easily elicit adverse reactions, such as gastrointestinal discomfort, addiction, dependence, and so on. Traditional Chinese medicine and its active ingredients have unique advantages in the treatment of pain for quite a long time, and many analgesic drugs directly or indirectly were isolatiedfrom Chinese medicine or natural products, such as Liu Suan Yan Hu Suo Yi Su Pian and aspirin. With the development and modernization of research on herbal medicine more and more studies have been conducted on the active ingredients and mechanisms of traditional Chinese medicine analgesics. However, no review has been done on analgesic active components and their mechanisms. In this paper, 81 active components with clear chemical structure and definite analgesic effects in vivo and in vitro of traditional Chinese medicine and mechanisms of action reported in recent literatures are reviewed and summarized to provide reference for clinical analgesia and analgesics research.

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“…These studies were never disproved experimentally, but sparked a debate and were the object of comments or critical commentaries concerning the action mechanisms of Gelsemium and the methods of its investigation [16] , [17] , [18] , [19] , [20] , [21] , [22] . In the meantime, the effect of Gelsemium or its alkaloids in neurological and behavioral models were reported by several independent laboratories [1] , [23] , [24] , [25] , [26] , [27] , [28] . Due to the complexity and novelty of the topic, several aspects deserve clarification and the main issues of this debate are here summarized.…”

Section: Introductionmentioning

confidence: 99%

Experimental neuropharmacology of Gelsemium sempervirens : Recent advances and debated issues

Bellavite

Bonafini

Marzotto

2018

Journal of Ayurveda and Integrative Medicine

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Gelsemium sempervirens L. (Gelsemium) is traditionally used for its anxiolytic-like properties and its action mechanism in laboratory models are under scrutiny. Evidence from rodent models was reported suggesting the existence of a high sensitivity of central nervous system to anxiolytic power of Gelsemium extracts and Homeopathic dilutions. In vitro investigation of extremely low doses of this plant extract showed a modulation of gene expression of human neurocytes. These studies were criticized in a few commentaries, generated a debate in literature and were followed by further experimental studies from various laboratories. Toxic doses of Gelsemium cause neurological signs characterized by marked weakness and convulsions, while ultra-low doses or high Homeopathic dilutions counteract seizures induced by lithium and pilocarpine, decrease anxiety after stress and increases the anti-stress allopregnanolone hormone, through glycine receptors. Low (non-Homeopathic) doses of this plant or its alkaloids decrease neuropathic pain and c-Fos expression in mice brain and oxidative stress. Due to the complexity of the matter, several aspects deserve interpretation and the main controversial topics, with a focus on the issues of high dilution pharmacology, are discussed and clarified.

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Functional modulation of glycine receptors by the alkaloid gelsemine

Cited by 39 publications

References 61 publications

Modulation of glycine receptor single-channel conductance by intracellular phosphorylation

Modulation of glycine receptor single-channel conductance by intracellular phosphorylation

Progress on Active Analgesic Components and Mechanisms of Commonly Used Traditional Chinese Medicines: A Comprehensive Review

Experimental neuropharmacology of Gelsemium sempervirens : Recent advances and debated issues

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