Browsing by Subject "G-protein"

Now showing 1 - 3 of 3
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    Expression and localization of RGS9-2/G 5/R7BP complex in vivo is set by dynamic control of its constitutive degradation by cellular cysteine proteases
    (Society for Neuroscience, 2007-12-19) Anderson, Garret R.; Lujan, Rafael; Semenov, Arthur; Pravetoni, Marco; Posokhova, Ekaterina N.; Song, Joseph H.; Uversky, Vladimir; Chen, Ching-Kang; Wickman, Kevin; Martemyanov, Kirill A.; Biochemistry and Molecular Biology, School of Medicine
    A member of regulator of G-protein signaling family, RGS9-2, is an essential modulator of signaling through neuronal dopamine and opioid G-protein-coupled receptors. Recent findings indicate that the abundance of RGS9-2 determines sensitivity of signaling in the locomotor and reward systems in the striatum. In this study we report the mechanism that sets the concentration of RGS9-2 in vivo, thus controlling G-protein signaling sensitivity in the region. We found that RGS9-2 possesses specific degradation determinants which target it for constitutive destruction by lysosomal cysteine proteases. Shielding of these determinants by the binding partner R7 binding-protein (R7BP) controls RGS9-2 expression at the posttranslational level. In addition, binding to R7BP in neurons targets RGS9-2 to the specific intracellular compartment, the postsynaptic density. Implementation of this mechanism throughout ontogenetic development ensures expression of RGS9-2/type 5 G-protein beta subunit/R7BP complexes at postsynaptic sites in unison with increased signaling demands at mature synapses.
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    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.
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    Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors
    (Frontiers Media, 2021-11-18) Muñoz, Braulio; Mariqueo, Trinidad; Murath, Pablo; Peters, Christian; Yevenes, Gonzalo E.; Moraga-Cid, Gustavo; Peoples, Robert W.; Aguayo, Luis G.; Pharmacology and Toxicology, School of Medicine
    Alpha1-containing glycine receptors (GlyRs) are major mediators of synaptic inhibition in the spinal cord and brain stem. Recent studies reported the presence of α2-containing GlyRs in other brain regions, such as nucleus accumbens and cerebral cortex. GlyR activation decreases neuronal excitability associated with sensorial information, motor control, and respiratory functions; all of which are significantly altered during ethanol intoxication. We evaluated the role of β GlyR subunits and of two basic amino acid residues, K389 and R390, located in the large intracellular loop (IL) of the α2 GlyR subunit, which are important for binding and functional modulation by Gβγ, the dimer of the trimeric G protein conformation, using HEK-293 transfected cells combined with patch clamp electrophysiology. We demonstrate a new modulatory role of the β subunit on ethanol sensitivity of α2 subunits. Specifically, we found a differential allosteric modulation in homomeric α2 GlyRs compared with the α2β heteromeric conformation. Indeed, while α2 was insensitive, α2β GlyRs were substantially potentiated by ethanol, GTP-γ-S, propofol, Zn2+ and trichloroethanol. Furthermore, a Gβγ scavenger (ct-GRK2) selectively attenuated the effects of ethanol on recombinant α2β GlyRs. Mutations in an α2 GlyR co-expressed with the β subunit (α2AAβ) specifically blocked ethanol sensitivity, but not propofol potentiation. These results show a selective mechanism for low ethanol concentration effects on homomeric and heteromeric conformations of α2 GlyRs and provide a new mechanism for ethanol pharmacology, which is relevant to upper brain regions where α2 GlyRs are abundantly expressed.