Browsing by Subject "Ligand-gated ion channels"

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Endogenous, exogenous and novel allosteric modulators of ligand-gated ion channels
(2019-01-28) Pflanz, Natasha Christina; Mihic, S. John; Mukhopadhyay, Somshuvra; Wilcox, Richard; Pierce, Jonathan; Gonzales, Rueben
The central nervous system is a web of neuronal communication, mediated through excitatory and inhibitory signals. These signals are mediated in part by the amino acid neurotransmitters glutamate, GABA and glycine, which are ligands for specific ligand-gated ion channels. While direct activation or inactivation of ligand-gated ion channels can cause marked and sometimes detrimental changes in the nervous system, allosteric modulators of these channels can produce more subtle and specific changes. Despite the clinical potential of allosteric modulators, the molecular mechanisms of their action at ligand-gated ion channels are poorly understood. This dissertation covers several aspects of allosteric modulation: elucidating the molecular mechanism of known exogenous modulators, identifying endogenous compounds as modulators, and using a drug discovery technique to find novel modulators. The first chapter details how ketone bodies are endogenous allosteric modulators of NMDA, GABA [subscript A] and glycine receptor function, and that this action of ketone bodies may underlie therapeutic benefits. Next, I characterize how benzodiazepines, acting as positive allosteric modulators of the GABA [subscript A] receptor, produce a molecular rearrangement in the GABA [subscript A] receptor resulting in an enhancement in receptor function. This involves an interaction between charged residues at the interface of adjacent subunits of the GABA [subscript A] receptor. Finally, I utilize phage display technology to identify peptides capable of allosteric modulation of the GABA [subscript A] receptor, providing evidence that this technique can be used to identify new compounds for a large range of indications.
Molecular Mechanism for the Dual Alcohol Modulation of Cys-loop Receptors
(Public Library of Science, 2012-10-04) Murail, Samuel; Howard, Rebecca J.; Broemstrup, Torben; Bertaccini, Edward J.; Harris, R. Adron; Trudell, James R.; Lindahl, Erik
Cys-loop receptors constitute a superfamily of pentameric ligand-gated ion channels (pLGICs), including receptors for acetylcholine, serotonin, glycine and γ-aminobutyric acid. Several bacterial homologues have been identified that are excellent models for understanding allosteric binding of alcohols and anesthetics in human Cys-loop receptors. Recently, we showed that a single point mutation on a prokaryotic homologue (GLIC) could transform it from a channel weakly potentiated by ethanol into a highly ethanol-sensitive channel. Here, we have employed molecular simulations to study ethanol binding to GLIC, and to elucidate the role of the ethanol-enhancing mutation in GLIC modulation. By performing 1-µs simulations with and without ethanol on wild-type and mutated GLIC, we observed spontaneous binding in both intra-subunit and inter-subunit transmembrane cavities. In contrast to the glycine receptor GlyR, in which we previously observed ethanol binding primarily in an inter-subunit cavity, ethanol primarily occupied an intra-subunit cavity in wild-type GLIC. However, the highly ethanol-sensitive GLIC mutation significantly enhanced ethanol binding in the inter-subunit cavity. These results demonstrate dramatic effects of the F(14′)A mutation on the distribution of ligands, and are consistent with a two-site model of pLGIC inhibition and potentiation.