Medicine and Health Sciences Commons^™

A Selective Gβγ-Linked Intracellular Mechanism For Modulation Of A Ligand-Gated Ion Channel By Ethanol, Gonzalo E. Yevenes, Gustavo Moraga-Cid, Robert W. Peoples, Günther Schmalzing, Luis G. Aguayo

Biomedical Sciences Faculty Research and Publications

The current understanding about ethanol effects on the ligand-gated ion channel (LGIC) superfamily has been restricted to identify potential binding sites within transmembrane (TM) domains in the Cys-loop family. Here, we demonstrate a key role of the TM3–4 intracellular loop and Gβγ signaling for potentiation of glycine receptors (GlyRs) by ethanol. We discovered 2 motifs within the large intracellular loop of the GlyR α₁ subunit that are critical for the actions of pharmacological concentrations of ethanol. Significantly, the sites were ethanol-specific because they did not alter the sensitivity to general anesthetics, neurosteroids, or longer n-alcohols. Furthermore, Gβγ scavengers …

Evidence That Α2-Antiplasmin Becomes Covalently Ligated To Plasma Fibrinogen In The Circulation: A New Role For Plasma Factor Xiii In Fibrinolysis Regulation, Michael W. Mosesson, Kevin R. Siebenlist, Irene Hernandez, K. N. Lee, V. J. Christiansen, P. A. Mckee

Biomedical Sciences Faculty Research and Publications

Background:

Plasma alpha₂-antiplasmin (α₂AP) is a rapid and effective inhibitor of the fibrinolytic enzyme plasmin. Congenital α₂AP deficiency results in a severe hemorrhagic disorder due to accelerated fibrinolysis. It is well established that in the presence of thrombin-activated factor XIII (FXIIIa), α₂AP becomes covalently ligated to the distal α chains of fibrin or fibrinogen at lysine 303 (two potential sites per molecule). Some time ago we showed that α₂AP is covalently linked to plasma fibrinogen . That singular observation led to our hypothesis that native plasma factor XIII (FXIII), …

Blunted Cystine–Glutamate Antiporter Function In The Nucleus Accumbens Promotes Cocaine-Induced Drug Seeking, Kristen S. Kau, Aric Madayag, John R. Mantsch, Mark D. Grier, Omer Abdulhameed, David A. Baker

Biomedical Sciences Faculty Research and Publications

Repeated cocaine alters glutamate neurotransmission, in part, by reducing cystine–glutamate exchange via system x_c−, which maintains glutamate levels and receptor stimulation in the extrasynaptic compartment. In the present study, we undertook two approaches to determine the significance of plasticity involving system x_c−. First, we examined whether the cysteine prodrug N-acetylcysteine attenuates cocaine-primed reinstatement by targeting system x_c−. Rats were trained to self-administer cocaine (1 mg/kg/200 μl, i.v.) under extended access conditions (6 h/day). After extinction training, cocaine (10 mg/kg, i.p.) primed reinstatement was assessed in rats pretreated with N-acetylcysteine (0–60 mg/kg, i.p.) in the …

Functional Interactions Of Alcohol-Sensitive Sites In The N-Methyl-D-Aspartate Receptor M3 And M4 Domains, Hong Ren, Abdelghaffar K. Salous, Jaclyn M. Paul, Kaitlin A. Lamb, Donard S. Dwyer, Robert W. Peoples

Biomedical Sciences Faculty Research and Publications

The N-methyl-d-aspartate receptor is an important mediator of the behavioral effects of ethanol in the central nervous system. Previous studies have demonstrated sites in the third and fourth membrane-associated (M) domains of the N-methyl-d-aspartate receptor NR2A subunit that influence alcohol sensitivity and ion channel gating. We investigated whether two of these sites, Phe-637 in M3 and Met-823 in M4, interactively regulate the ethanol sensitivity of the receptor by testing dual substitution mutants at these positions. A majority of the mutations decreased steady-state glutamate EC₅₀ values and maximal steady-state to peak current ratios (I_ss/I …

Stressor- And Corticotropin Releasing Factor-Induced Reinstatement And Active Stress-Related Behavioral Responses Are Augmented Following Long-Access Cocaine Self-Administration By Rats, John R. Mantsch, David A. Baker, David M. Francis, Eric S. Katz, Michael A. Hoks, Joseph P. Serge

Biomedical Sciences Faculty Research and Publications

Rationale Stressful events during periods of drug abstinence likely contribute to relapse in cocaine-dependent individuals. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) responsiveness.

Objectives This study examined stressor- and CRF-induced cocaine seeking and other stress-related behaviors in rats with different histories of cocaine self-administration (SA).

Materials and methods Rats self-administered cocaine under short-access (ShA; 2 h daily) or long-access (LgA; 6 h daily) conditions for 14 days or were provided access to saline and were tested for reinstatement by a stressor (electric footshock), cocaine or an icv injection of CRF and …