MSTPublications: August 2018
Congratulations to all of our MSTP students on their successful publications! Take a look at the great work our students are doing.
Dorsal BNST α2A-adrenergic receptors produce HCN-dependent excitatory actions that initiate anxiogenic behaviors.
Harris NA, Isaac AT, Günther A, Merkel K, Melchior J, Xu M, Eguakun E, Perez R, Nabit BP, Flavin S, Gilsbach R, Shonesy B, Hein L, Abel T, Baumann A, Matthews R, Centanni SW, Winder DG.
J Neurosci. 2018 Aug 27. pii: 0963-18. doi: 10.1523/JNEUROSCI.0963-18.2018. [Epub ahead of print]
Stress is a precipitating agent in neuropsychiatric disease and initiates relapse to drug-seeking behavior in addicted patients. Targeting the stress system in protracted abstinence from drugs of abuse with anxiolytics may be an effective treatment modality for substance use disorders. α2A-adrenergic receptors (α2A-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α2A-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α2A-ARs play important roles in stress-responses, but their cellular mechanisms of action are unclear. In humans, the α2A-AR agonist guanfacine reduces overall craving and uncouples craving from stress yet minimally affects relapse, potentially due to competing actions in the brain. Here we show that heteroceptor α2A-ARs postsynaptically enhance dorsal BNST (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels, as inhibition of these channels is necessary and sufficient for excitatory actions. Finally, this excitatory action is mimicked by clozapine-N-oxide activation of the Gi-coupled DREADD hM4Di in dBNST neurons, and its activation elicits anxiety-like behavior in the elevated plus maze. Together, this data provides a framework for elucidating cell-specific actions of GPCR signaling and provides a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction.
Discovery and Characterization of VU0529331, a Synthetic Small-Molecule Activator of Homomeric G Protein-gated, Inwardly-rectifying, Potassium (GIRK) Channels.
Kozek KA, Du Y, Sharma S, Prael FJ, Spitznagel BD, Kharade SV, Denton JS, Hopkins CR, Weaver CD.
ACS Chem Neurosci. 2018 Aug 23. doi: 10.1021/acschemneuro.8b00287. [Epub ahead of print]
G protein-gated, inwardly-rectifying, potassium (GIRK) channels are important regulators of cellular excitability throughout the body. GIRK channels are heterotetrameric and homotetrameric combinations of the Kir3.1-4 (GIRK1-4) subunits. Different subunit combinations are expressed throughout the central nervous system (CNS) and the periphery, and most of these combinations contain a GIRK1 subunit. For example, the predominance of GIRK channels in the CNS are comprised of GIRK1 and GIRK2 subunits, while the GIRK channels in cardiac atrial myocytes are made up mostly of GIRK1 and GIRK4 subunits. Although the vast majority of GIRK channels contain a GIRK1 subunit, discrete populations of cells that express non-GIRK1-containing GIRK (non-GIRK1/X) channels do exist. For instance, dopaminergic neurons in the ventral tegmental area of the brain, associated with addiction and reward, do not express the GIRK1 subunit. Targeting these non-GIRK1/X channels with subunit-selective pharmacological probes could lead to important insights into how GIRK channels are involved in reward and addiction. Such insights may, in turn, reveal therapeutic opportunities for the treatment or prevention of addiction. Previously, our laboratory discovered small molecules that can specifically modulate the activity of GIRK1-containing GIRK channels. However, efforts to generate compounds active on non-GIRK1/X channels from these scaffolds have been unsuccessful. Recently, ivermectin was shown to modulate non-GIRK1/X channels, and historically, ivermectin is known to modulate a wide variety of neuronal channels and receptors. Further, ivermectin is a complex natural product, which makes it a challenging starting point for development of more selective, effective, and potent compounds. Thus, while ivermectin provides proof-of-concept as a non-GIRK1/X channel activator, it is of limited utility. Therefore, we sought to discover a synthetic small molecule that would serve as a starting point for the development of non-GIRK1/X channel modulators. To accomplish this, we used a high-throughput thallium flux assay to screen a 100,000-compound library in search of activators of homomeric GIRK2 channels. Using this approach, we discovered VU0529331, the first synthetic small molecule reported to activate non-GIRK1/X channels, to our knowledge. This discovery represents the first step towards developing potent and selective non-GIRK1/x channel probes. Such molecules will help elucidate the role of GIRK channels in addiction, potentially establishing a foundation for future development of therapies utilizing targeted GIRK channel modulation.
Bile diversion, a bariatric surgery, and bile acid signaling reduce central cocaine reward.
Reddy IA, Smith NK, Erreger K, Ghose D, Saunders C, Foster DJ, Turner B, Poe A, Albaugh VL, McGuinness O, Hackett TA, Grueter BA, Abumrad NN, Flynn CR, Galli A.
PLoS Biol. 2018 Jul 26;16(7):e2006682. doi: 10.1371/journal.pbio.2006682. eCollection 2018 Jul.
Communication between the gut and the brain is increasingly being appreciated as influencing motivated behavior. The gut can influence brain function through secreted hormones traveling through the blood and entering the brain. We utilize a weight-loss surgery designed to elevate one class of circulating hormones, bile acids, to show their action in the brain and their role in modulating behaviors associated with the addictive properties of cocaine. This surgery reduces the reward-related behavior and the psychomotor effects of cocaine. Furthermore, we utilize a knockout mouse model to reveal that a specific bile acid receptor mediates some of the effects of bile acids over motivated behavior. Viral intervention studies localize this effect to a receptor population within the nucleus accumbens, a brain region central to the processing of reward. These findings identify a role for bile acids in blunting cocaine’s ability to alter brain function, generating novel and exciting directions for the treatment of cocaine abuse.
The PGI2 Analog Cicaprost Inhibits IL-33-Induced Th2 Responses, IL-2 Production, and CD25 Expression in Mouse CD4+ T Cells.
Zhou W, Zhang J, Toki S, Goleniewska K, Johnson MO, Bloodworth MH, Newcomb DC, Peebles RS Jr.
J Immunol. 2018 Aug 20. pii: ji1700605. doi: 10.4049/jimmunol.1700605. [Epub ahead of print]
Cortical projections to the two retinotopic maps of primate pulvinar are distinct.
Moore B, Li K, Kaas JH, Liao CC, Boal AM, Mavity-Hudson J, Casagrande V.
J Comp Neurol. 2018 Aug 5. doi: 10.1002/cne.24515. [Epub ahead of print]
Reovirus σNS and μNS Proteins Remodel the Endoplasmic Reticulum to Build Replication Neo-Organelles.
Tenorio R, Fernández de Castro I, Knowlton JJ, Zamora PF, Lee CH, Mainou BA, Dermody TS, Risco C.
MBio. 2018 Aug 7;9(4). pii: e01253-18. doi: 10.1128/mBio.01253-18.
Applications of Immunopharmacogenomics: Predicting, Preventing, and Understanding Immune-Mediated Adverse Drug Reactions.
Karnes JH, Miller MA, White KD, Konvinse KC, Pavlos RK, Redwood AJ, Peter JG, Lehloenya R, Mallal SA, Phillips EJ.
Annu Rev Pharmacol Toxicol. 2018 Aug 22. doi: 10.1146/annurev-pharmtox-010818-021818. [Epub ahead of print]
Regulation of energy rheostasis by the melanocortin-3 receptor.
Ghamari-Langroudi M, Cakir I, Lippert RN, Sweeney P, Litt MJ, Ellacott KLJ, Cone RD.
Sci Adv. 2018 Aug 22;4(8):eaat0866. doi: 10.1126/sciadv.aat0866. eCollection 2018 Aug.
Quis Custodiet Ipsos Custodes? Regulation of Cell-Mediated Immune Responses Following Viral Lung Infections.
Rogers MC, Williams JV.
Annu Rev Virol. 2018 Jul 27. doi: 10.1146/annurev-virology-092917-043515. [Epub ahead of print]
Healthy Donor Polyclonal IgM’s Diminish B Lymphocyte Autoreactivity, Enhance Treg Generation, and Reverse T1D in NOD Mice.
Wilson CS, Chhabra P, Marshall AF, Morr CV, Stocks BT, Bonami RH, Poffenberger G, Brayman KL, Moore DJ.
Diabetes. 2018 Aug 21. pii: db180456. doi: 10.2337/db18-0456. [Epub ahead of print]
Relationship between very low low-density lipoprotein cholesterol concentrations not due to statin therapy and risk of type 2 diabetes: A US-based cross-sectional observational study using electronic health records.
Feng Q, Wei WQ, Chung CP, Levinson RT, Sundermann AC, Mosley JD, Bastarache L, Ferguson JF, Cox NJ, Roden DM, Denny JC, Linton MF, Edwards DRV, Stein CM.
PLoS Med. 2018 Aug 28;15(8):e1002642. doi: 10.1371/journal.pmed.1002642. eCollection 2018 Aug.