Department of Pharmacology and Toxicology Works

Permanent URI for this collection

https://hdl.handle.net/1805/6758

Browse

Browsing Department of Pharmacology and Toxicology Works by Author "Aguayo, Luis G."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Influence of nonsynaptic α1 glycine receptors on ethanol consumption and place preference
    (Wiley, 2019-03-18) Muñoz, Braulio; Gallegos, Scarlet; Peters, Christian; Murath, Pablo; Lovinger, David M.; Homanics, Gregg E.; Aguayo, Luis G.; Pharmacology and Toxicology, School of Medicine
    Alcohol abuse leads to great medical, social, and economic burdens throughout the world. It is believed that the rewarding actions of alcohol are mediated by alterations in the mesolimbic dopaminergic system leading to increased levels of dopamine in the nucleus accumbens (nAc). Little is known about the role that ligand gated ion channels (LGIC), such as glycine receptors (GlyR), have in regulating levels of ethanol intake and place preference. In this study, we used Knock-in (KI) mice that have ethanol insensitive α1 GlyRs (KK385/386AA) and a combination of electrophysiological and behavioral approaches to examine how expression of ethanol resistant α1 GlyRs in brain neurons might affect binge drinking and conditioned place preference. Data show that tonic α1 GlyR-mediated currents that modulate accumbal excitability were exclusively sensitive to ethanol only in WT mice. Behavioral studies showed that the KI mice have a higher intake of ethanol upon first exposure to drinking and greater conditioned place preference to ethanol, suggesting that α1 GlyRs in the brain have a protective role against abuse. This study suggests that non-synaptic α1 containing GlyRs have a role in motivational and early reinforcing effects of ethanol and opens a novel opportunity for pharmacotherapy development to treat alcohol use disorders.
  • Thumbnail Image
    Item
    Modulation of glycine receptor single-channel conductance by intracellular phosphorylation
    (Springer Nature, 2020) Moraga-Cid, Gustavo; San Martín, Victoria P.; Lara, Cesar O.; Muñoz, Braulio; Marileo, Ana M.; Sazo, Anggelo; Muñoz-Montesino, Carola; Fuentealba, Jorge; Castro, Patricio A.; Guzmán, Leonardo; Burgos, Carlos F.; Zeilhofer, Hanns U.; Aguayo, Luis G.; Corringer, Pierre-Jean; Yévenes, Gonzalo E.; Pharmacology and Toxicology, School of Medicine
    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 PKA-dependent 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 PKA-targeted 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.