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Ivermectin
Published in Sarah H. Wakelin, Howard I. Maibach, Clive B. Archer, Handbook of Systemic Drug Treatment in Dermatology, 2015
Francisco Vega-Lopez, Sara Ritchie
Ivermectin acts against helminths and arthropods by activating glutamate-gated chloride channels. These receptors are found exclusively in invertebrate nerve and muscle cells and belong to the pentameric cys-loop receptor family of ligand-gated ion channels. Ivermectin binding causes ion channel disruption leading to cell death, and the receptor specificity explains the drug’s high efficacy and tolerability in humans. High concentrations of ivermectin can cross the blood–brain barrier and can bind to vertebrate gamma-aminobutyric acid (GABA) type A and glycine receptors. This can cause GABA-mimetic toxicity with hypotension, respiratory failure, coma, and even death.
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
GABAA receptors belong to the Cys-loop superfamily of receptors, which also includes glycine, nicotinic acetylcholine, and 5-HT3 receptors. These ligand-gated channels are comprised of five subunits, each of which has four transmembrane domains. In contrast, glutamate receptors bear no sequence similarity to Cys-loop receptors and are believed to be comprised of four subunits, each of which has three transmembrane domains, as well as a hydrophobic reentrant loop that dips into the membrane but does not cross.16 The NMDA receptor is of particular interest in that it is thought to play a critical role in learning, as well as in a number of pathological processes, including stroke and neurodegenerative diseases.17,18
Inter- and Intracellular Signaling in Plant Cells with Participation of Neurotransmitters (Biomediators)
Published in Akula Ramakrishna, Victoria V. Roshchina, Neurotransmitters in Plants, 2018
Reception both on the plasmatic membranes in cell-acceptor occurs when any transmitter acts outside and on the outer membrane of an organelle received from the neuromediator within the cell. It is known that some of molecules carry signals over long distances, whereas others act locally to convey information between neighboring cells. Moreover, signaling molecules differ in their mode of action on their target cells. Like animals, there are plant surface receptors for neurotransmitters. Cholinoreceptors in mammals have been distinguished in two main types with subtypes, depending on the sensitivity of the reactions to agonists of acetylcholine, such as nicotine or muscarine, and are called nicotinic or muscarinic receptors, respectively. For acetylcholine in plant cells, pharmacological analysis with its agonists nicotine or muscarine showed the presence of nicotinic or muscarinic types of cholinoreceptors or receptors with mixed characteristics (Roshchina 2001). Nicotinic receptors of animals were characterized by molecular biologists (Piccioto et al. 1998; Corringer et al. 2000), including some ionic channels related to the receptors (Pichon 1993). The dopamine receptors have been classified into two groups, the D1-like and D2-like dopamine receptors, respectively, based on molecular biology and pharmacological studies as well the gene structures of the receptors (D’Souza 2015). The gene structures of these two classes of receptors are dissimilar with respect to the organization of their coding and regulatory regions. Biogenic amines also have receptors called adrenoreceptors (Lanier and Limbird 1997), serotonin receptors (Davis et al. 2002), and histamine receptors (Parsons and Ganellin 2006), which are described in literature devoted to mammalians. In animals, there is a known receptor part (this class of ligand binding ion channels called Cys-loop receptors protein) for acetylcholine, serotonin, and GABA that plays a major role in fast synaptic transmission and also known in prokaryotes.
Glycine transporter-1 inhibitors: a patent review (2011–2016)
Published in Expert Opinion on Therapeutic Patents, 2018
Glycine also facilitates fast synaptic inhibitory neurotransmission within the CNS via stimulation of strychnine-sensitive GlyRs, which are cysteine-loop (Cys-loop) receptor family ligand-gated ion channels [21]. GlyR-mediated neurotransmission is principally involved in motor and reflex activity, muscle tone, respiratory rhythms, and sensory sensation [22]. Expression of these receptors is largely restricted within caudal regions of the CNS (i.e. cerebellum [23], brain stem [24], and spinal cord [25]) and in the retina [26]. Binding of 1 at the GlyR glycine-A binding induces channel pore opening with concomitant chloride influx and subsequent neuronal hyperpolarization, resulting in inhibition of action potential generation [21]. Studies suggest that enhancing glycinergic inhibitory neurotransmission will dampen the reinforcing effects associated with increased ethanol-induced dopamine release in the nucleus accumbens, thus providing an approach to treat addiction [27,28]. Augmentation of GlyR activity has also recently begun to garner significant attention as a means by which to obtund spinal nociceptive signaling and treat various modalities of chronic pain [29,30].
Ion channels as therapeutic antibody targets
Published in mAbs, 2019
Catherine J. Hutchings, Paul Colussi, Theodore G. Clark
Amgen has described the targeting of Glycine Receptor α3 (GlyRα3), a Cys-loop receptor class ion channel implicated in pain. Glycine binding to the ECD triggers a conformational change, opening the ion channel to chloride ions. A specific antibody, AM-3607, directed to GlyRα3 was shown to enhance the response to exogenous glycine and was used in structural studies in complex with the pentameric GlyRα3 to further understand potentiator mechanism. The resulting crystal structure was resolved to 2.6Å, revealing that the mAb binding site was 10Å above the agonist binding site, suggesting a novel positive allosteric binding site.379 Whilst this provides valuable insights for structure-based drug discovery, no further therapeutic development is planned for this mAb.
Spider toxins targeting ligand-gated ion channels
Published in Toxin Reviews, 2021
Together with nAChRs, serotonine (5-HT3), glycine, gamma-aminobutyric acid A (GABAA) receptors, and zinc-activated channels belong to the superfamily of cys-loop receptors. However, there are no reports on spider toxin targeting aforementioned receptors.