Potentiation of Gamma Aminobutyric Acid Receptors (GABAAR) by Ethanol: How Are Inhibitory Receptors Affected?

Förstera, Benjamín; Castro, Patricio; Moraga-Cid, Gustavo; Aguayo, Luis G.

doi:10.3389/fncel.2016.00114

Cited by 50 publications

(47 citation statements)

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“…Ionotropic Glutamate Receptors (iGluRs) are ligand-gated ion channels (LGICs), which are well characterized targets for EtOH actions (Forstera et al, 2016; Lovinger, 1997; Szumliski and Woodward, 2014; Vengeliene et al, 2008). LGICs are heteromeric proteins that bind extracellular neurotransmitters or intracellular messengers and transduce that binding energy into the opening of an intrinsic ion pore (Collingridge et al, 2009).…”

Section: 1 Glutamate and Etoh Effectsmentioning

confidence: 99%

“…There are 3 main types of GABA receptors; GABA A R and GABA C R are LGICs, while the GABA B R is a GPCR (Aguayo et al, 2002; Forstera et al, 2016; Harris, 1999; Lovinger, 1997). Early rodent studies showed that systemic administration of GABA A R agonists increased voluntary EtOH consumption, whereas GABA A R antagonists and benzodiazepine inverse agonists decreased drinking (Boyle et al, 1993; Rassnick et al, 1993).…”

Section: 2 Gaba and Etoh Effectsmentioning

confidence: 99%

“…Other “cys-loop” LGICs include the strychnine-sensitive glycine receptor (GlyR), nicotinic acetylcholine receptor (nAChR) and serotonin 3 receptor (5-HT 3 ). Acute EtOH tends to enhance cys-loop LGIC function (Aguayo et al, 2002; Forstera et al, 2016; Harris, 1999; Lovinger, 1997) by increasing their probability of channel opening and/or increasing agonist affinity (Tonner and Miller, 1995; Welsh et al, 2009). This EtOH effect has been observed in both synaptic and extrasynaptic receptors (Eggers and Berger, 2004; Sebe et al, 2003; Ye et al, 2001; Ziskind-Conhaim et al, 2003).…”

Section: 2 Gaba and Etoh Effectsmentioning

confidence: 99%

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Synaptic targets: Chronic alcohol actions

2017

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Alcohol acts on numerous cellular and molecular targets to regulate neuronal communication within the brain. Chronic alcohol exposure and acute withdrawal generate prominent neuroadaptations at synapses, including compensatory effects on the expression, localization and function of synaptic proteins, channels and receptors. The present article reviews the literature describing the synaptic effects of chronic alcohol exposure and their relevance for synaptic transmission in the central nervous system. This review is not meant to be comprehensive, but rather to highlight the effects that have been observed most consistently and that are thought to contribute to the development of alcohol dependence and the negative aspects of withdrawal. Specifically, we will focus on the major excitatory and inhibitory neurotransmitters in the brain, glutamate and GABA, respectively, and how their neuroadaptations after chronic alcohol exposure contributes to alcohol reinforcement, dependence and withdrawal.

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Section: 1 Glutamate and Etoh Effectsmentioning

confidence: 99%

Section: 2 Gaba and Etoh Effectsmentioning

confidence: 99%

Section: 2 Gaba and Etoh Effectsmentioning

confidence: 99%

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Synaptic targets: Chronic alcohol actions

2017

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“…The complexity of alcohol action, however, has presented a great challenge for mechanistic investigation. Alcohols act on various proteins by different mechanisms (Deitrich et al, 1989; Forstera et al, 2016). Pentameric ligandgated ion channels (pLGICs) in the CNS, which include the inhibitory glycine receptors (GlyRs) and γ-aminobutyric acid type A receptors (GABA A Rs), and the excitatory serotonin receptors (5HT 3 Rs) and nicotinic acetylcholine receptors (nAChRs), are plausible molecular targets of linear alcohols ( n -alcohols).…”

Section: Introductionmentioning

confidence: 99%

Structural Basis of Alcohol Inhibition of the Pentameric Ligand-Gated Ion Channel ELIC

et al. 2017

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“…The complexity of alcohol action, however, has presented a great challenge for mechanistic investigation. Alcohols act on various proteins by different mechanisms (Deitrich et al, 1989;Forstera et al, 2016). Pentameric ligandgated ion channels (pLGICs) in the CNS, which include the inhibitory glycine receptors (GlyRs) and γ-aminobutyric acid type A receptors (GABA A Rs), and the excitatory serotonin receptors (5HT 3 Rs) and nicotinic acetylcholine receptors (nAChRs), are plausible molecular targets of linear alcohols (nalcohols).…”

Section: Introductionmentioning

confidence: 99%

Structural Basis of Alcohol Inhibition of the Pentameric Ligand-Gated Ion Channel ELIC

Chen

Wells

Tillman

et al. 2017

Biophysical Journal

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SUMMARYThe structural basis for alcohol modulation of neuronal pentameric ligand-gated ion channels (pLGICs) remains elusive. We determined an inhibitory mechanism of alcohol on the pLGIC Erwinia chrysanthemi (ELIC) through direct binding to the pore. X-ray structures of ELIC cocrystallized with 2-bromoethanol, in both the absence and presence of agonist, reveal 2-bromoethanol binding in the pore near T237(6′) and the extracellular domain (ECD) of each subunit at three different locations. Binding to the ECD does not appear to contribute to the inhibitory action of 2-bromoethanol and ethanol as indicated by the same functional responses of wild-type ELIC and mutants. In contrast, the ELIC-α1β3GABA A R chimera, replacing the ELIC transmembrane domain (TMD) with the TMD of α1β3GABA A R, is potentiated by 2-bromoethanol and ethanol. The results suggest a dominant role of the TMD in modulating alcohol effects. The X-ray structures and functional measurements support a pore-blocking mechanism for inhibitory action of short chain alcohols. *Correspondence and lead contact: Pei Tang: ptang@pitt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCESSION NUMBERSCrystal structures of BrEtOH-bound ELIC with (5SXU) and without (5SXV) PPA are deposited in the PDB. SUPPLEMENTAL INFORMATIONFigs. S1-3, Table S1, and experimental details. AUTHOR CONTRIBUTIONSQC conducted most of the experiments and analyzed the results. TST and MMW performed TEVC measurements and participated in manuscript preparation. MNK expressed and prepared ELIC mutants for functional studies. AC along with QC contributed to X-ray data collection. YX and PT designed the project. PT and QC wrote the manuscript. All authors reviewed the results and approved the final version of the manuscript.The authors declare no conflicts of interest with the contents of this article. HHS Public Access

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Potentiation of Gamma Aminobutyric Acid Receptors (GABAAR) by Ethanol: How Are Inhibitory Receptors Affected?

Cited by 50 publications

References 198 publications

Synaptic targets: Chronic alcohol actions

Synaptic targets: Chronic alcohol actions

Structural Basis of Alcohol Inhibition of the Pentameric Ligand-Gated Ion Channel ELIC

Structural Basis of Alcohol Inhibition of the Pentameric Ligand-Gated Ion Channel ELIC

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