Browsing by Subject "Adenosine"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Adenosinergic regulation of binge-like ethanol drinking and associated locomotor effects in male C57BL/6J mice
    (Elsevier, 2015-08) Fritz, Brandon M.; Boehm II, Stephen L.; Department of Psychology, School of Science
    We recently observed that the addition of caffeine (a nonselective adenosine receptor antagonist) to a 20% ethanol solution significantly altered the intoxication profile of male C57BL/6J (B6) mice induced by voluntary binge-like consumption in the 'Drinking-in-the-Dark' (DID) paradigm. In the current study, the roles of A1 and A2A adenosine receptor subtypes, specifically, in binge-like ethanol consumption and associated locomotor effects were explored. Adult male B6 mice (PND 60-70) were allowed to consume 20% ethanol (v/v) or 2% sucrose (w/v) for 6days via DID. On day 7, mice received a systemic administration (i.p.) of the A1 antagonist DPCPX (1, 3, 6mg/kg), the A2A antagonist MSX-3 (1, 2, 4mg/kg), or vehicle immediately prior to fluid access in DID. Antagonism of the A1 receptor via DPCPX was found to dose-dependently decrease binge-like ethanol intake and associated blood ethanol concentrations (p's<0.05), although no effect was observed on sucrose intake. Antagonism of A2A had no effect on ethanol or sucrose consumption, however, MSX-3 elicited robust locomotor stimulation in mice consuming either solution (p's<0.05). Together, these findings suggest unique roles for the A1 and A2A adenosine receptor subtypes in binge-like ethanol intake and its associated locomotor effects.
  • Thumbnail Image
    Item
    A protein-protein interaction underlies the molecular basis for substrate recognition by an adenosine-to-inosine RNA-editing enzyme
    (Oxford University Press, 2018-10-12) Rajendren, Suba; Manning, Aidan C.; Al-Awadi, Haider; Yamada, Kentaro; Takagi, Yuichiro; Hundley, Heather A.; Biochemistry and Molecular Biology, School of Medicine
    Adenosine deaminases that act on RNA (ADARs) convert adenosine to inosine within double-stranded regions of RNA, resulting in increased transcriptomic diversity, as well as protection of cellular double-stranded RNA (dsRNA) from silencing and improper immune activation. The presence of dsRNA-binding domains (dsRBDs) in all ADARs suggests these domains are important for substrate recognition; however, the role of dsRBDs in vivo remains largely unknown. Herein, our studies indicate the Caenorhabditis elegans ADAR enzyme, ADR-2, has low affinity for dsRNA, but interacts with ADR-1, an editing-deficient member of the ADAR family, which has a 100-fold higher affinity for dsRNA. ADR-1 uses one dsRBD to physically interact with ADR-2 and a second dsRBD to bind to dsRNAs, thereby tethering ADR-2 to substrates. ADR-2 interacts with >1200 transcripts in vivo, and ADR-1 is required for 80% of these interactions. Our results identify a novel mode of substrate recognition for ADAR enzymes and indicate that protein-protein interactions can guide substrate recognition for RNA editors.
  • Thumbnail Image
    Item
    Role of Adenosine A1 Receptors in Native Coronary Atherosclerosis, In-stent Stenosis, and Coronary Blood Flow Regulation in Metabolic Syndrome and Exercise
    (2010-04-08T13:47:08Z) Long, Xin; Sturek, Michael Stephen; Considine, Robert V.; Gunst, Susan J.; Herring, B. Paul; Tune, Johnathan D.
    Adenosine is widely thought to elicit coronary vasodilation and attenuate smooth muscle cell (SMC) proliferation, thereby providing cardioprotection. We cloned the porcine adenosine A1 receptor (A1R) subtype and found that it paradoxically stimulated proliferation of cultured coronary SMC by the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) signaling pathways, thus suggesting A1R dysregulation could play a role in coronary artery disease (CAD), restenosis, and regulation of coronary blood flow (CBF). We utilized the Ossabaw swine model of metabolic syndrome (MetS) to test the hypothesis that A1R activation contributes to development of CAD, in-stent stenosis, and CBF regulation. Swine were fed standard chow (Lean) or excess calorie atherogenic diet for over 20 weeks, which elicited MetS characteristics and coronary atherosclerosis compared to Lean. We observed increased A1R in native CAD in MetS, which was reversed by exercise training, and upregulation of A1R expression and A1R-ERK1/2 activation in an in vitro organ culture model of CAD. Intracoronary stent deployment followed by different durations of recovery showed A1R upregulation occurred before maximal in-stent stenosis in vi vivo. More importantly, selective A1R antagonism with 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX)-eluting stents decreased coronary ERK1/2 activation and reduced in-stent stenosis comparable to Taxus® (paclitaxel-eluting stents). A1R antagonism potentiated vasodilatory effects of some vasodilators other than adenosine in porcine coronary microcirculation under basal conditions. Short-term exercise training around stenting prevented stent-induced microvascular dysfunction and attenuated native atheroma in the genetically lean Yucatan swine. Conclusions: A1R upregulation and activation contributes to coronary in-stent stenosis in vivo in MetS, plays a role in the development of coronary atherosclerosis in vitro, and might involve in CBF dysregulation in dyslipidemia and stenting. Exercise training decreased A1R expression in atherosclerosis, reduced native atheroma, and prevented stent-induced microvascular dysfunction. Selective pharmacological antagonism of A1R holds promise for treatment of CAD.