Jürgen Wess

The National Institute of Diabetes and Digestive and Kidney Diseases, Maryland, United States

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Publications (259)1418.08 Total impact

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    ABSTRACT: Introduction Anticholinergics, blocking the muscarinic M3 receptor, are effective bronchodilators for patients with COPD. Recent evidence from M3 receptor deficient mice (M3R(-/-)) indicates that M3 receptors also regulate neutrophilic inflammation in response to cigarette smoke (CS). M3 receptors are present on almost all cell types and in this study we investigated the relative contribution of M3 receptors on structural cells versus inflammatory cells to CS-induced inflammation using bone-marrow chimeric mice. Methods Bone-marrow chimeras (C56Bl/6 mice) were generated and engraftment was confirmed after 10 weeks. Thereafter, irradiated and non-irradiated control animals were exposed to CS or fresh air for four consecutive days. Results CS induced a significant increase in neutrophil numbers in non-irradiated and irradiated control animals (4-35 fold). Interestingly, wild-type animals receiving M3R(-/-) bone marrow showed a similar increase in neutrophil number (15-fold). In contrast, no increase in the number of neutrophils was observed in M3R(-/-) animals receiving wild-type bone marrow. The increase in KC levels was similar in all smoke-exposed groups (2.5-5.0 fold). Micro-array analysis revealed that fibrinogen α and CD177, both involved in neutrophil migration, were downregulated in CS-exposed M3R(-/-) animals receiving wild-type bone marrow compared to CS-exposed wild-type animals, which was confirmed by RT-qPCR (1.6-2.5 fold). Conclusions These findings indicate that the M3 receptor on structural cells plays a pro-inflammatory role in CS-induced neutrophilic inflammation, whereas the M3 receptor on inflammatory cells does not. This effect is probably not mediated via KC release, but may involve altered adhesion and transmigration of neutrophils via fibrinogen α and CD177.
    American journal of physiology. Lung cellular and molecular physiology. 11/2014;
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    ABSTRACT: Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system. Prior to this study, the M1 mAChR subtype was viewed as the primary candidate for these actions relative to the other mAChR subtypes. Here we describe the discovery of a novel M4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties relative to other M4 PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801. VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M4 KO mice. VU0467154 also enhanced the acquisition of both contextual and cue-mediated fear conditioning when administered alone in wild-type mice. These novel findings suggest that M4 PAMs may provide a strategy for addressing the more complex affective and cognitive disruptions associated with schizophrenia and other neuropsychiatric disorders.
    ACS Chemical Neuroscience 08/2014; · 3.87 Impact Factor
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    ABSTRACT: The muscarinic acetylcholine receptors are a subfamily of G protein-coupled receptors that regulate numerous fundamental functions of the central and peripheral nervous system. The past few years have witnessed unprecedented new insights into muscarinic receptor physiology, pharmacology and structure. These advances include the first structural views of muscarinic receptors in both inactive and active conformations, as well as a better understanding of the molecular underpinnings of muscarinic receptor regulation by allosteric modulators. These recent findings should facilitate the development of new muscarinic receptor subtype-selective ligands that could prove to be useful for the treatment of many severe pathophysiological conditions.
    Nature reviews. Drug discovery. 06/2014;
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    ABSTRACT: Stimulation of muscarinic acetylcholine receptors (mAChRs) inhibits nociceptive transmission at the spinal level. However, it is unclear how each mAChR subtype regulates excitatory synaptic input from primary afferents. Here we examined excitatory postsynaptic currents (EPSCs) of dorsal horn neurons evoked by dorsal root stimulation in spinal cord slices from wild-type and mAChR subtype knockout (KO) mice. In wild-type mice, mAChR activation with oxotremorine-M decreased the amplitude of monosynaptic EPSCs in ~67% neurons but increased it in ~10% neurons. The inhibitory effect of oxotremorine-M was attenuated by the M2/M4 antagonist himbacine in the majority of neurons, and the remaining inhibition was abolished by group II/III metabotropic glutamate receptor (mGluR) antagonists in wild-type mice. In M2/M4 double-KO mice, oxotremorine-M inhibited monosynaptic EPSCs in significantly fewer neurons (~26%) and increased EPSCs in significantly more neurons (33%) compared with wild-type mice. Blocking group II/III mGluRs eliminated the inhibitory effect of oxotremorine-M in M2/M4 double-KO mice. In M2 single-KO and M4 single-KO mice, himbacine still significantly reduced the inhibitory effect of oxotremorine-M. However, the inhibitory and potentiating effects of oxotremorine-M on EPSCs in M3 single-KO and M1/M3 double-KO mice were similar to those in wild-type mice. In M5 single-KO mice, oxotremorine-M failed to potentiate evoked EPSCs, and its inhibitory effect was abolished by himbacine. These findings indicate that activation of presynaptic M2 and M4 subtypes reduces glutamate release from primary afferents. Activation of M5 subtype either directly increases primary afferent input or inhibits it through indirectly stimulating group II/III mGluRs.
    Journal of Biological Chemistry 04/2014; · 4.65 Impact Factor
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    ABSTRACT: Muscarinic acetylcholine receptor antagonists are widely used as bronchodilating drugs in pulmonary medicine. The therapeutic efficacy of these agents depends on the blockade of M3 muscarinic receptors expressed on airway smooth muscle cells. All muscarinic antagonists currently used as bronchodilating agents show high affinity for all five muscarinic receptor subtypes, thus increasing the likelihood of unwanted side effects. Recent X-ray crystallographic studies have provided detailed structural information about the nature of the orthosteric muscarinic binding site (the conventional acetylcholine binding site) and an 'outer' receptor cavity that can bind allosteric (non-orthosteric) drugs. These new findings should guide the development of selective M3 receptor blockers that have little or no effect on other muscarinic receptor subtypes.
    Current Opinion in Pharmacology 03/2014; 16C:24-30. · 5.44 Impact Factor
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    ABSTRACT: Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful due to the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wildtype mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic MRI. Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens, caudate-putamen, hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the nucleus accumbens and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in nucleus accumbens and caudate-putamen. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.Neuropsychopharmacology accepted article preview online, 20 January 2014. doi:10.1038/npp.2014.2.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2014; · 8.68 Impact Factor
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    ABSTRACT: Purpose: To test the hypothesis that the M3 muscarinic acetylcholine receptor subtype mediates cholinergic responses in murine ophthalmic arteries after endothelial removal. Methods:Muscarinic receptor gene expression was determined in ophthalmic arteries with intact and with removed endothelium using real-time PCR. To examine the role of the M3 receptor in mediating vascular responses, ophthalmic arteries from M3 receptor-deficient mice (M3R-/-) and respective wild-type controls were studied in vitro. Functional studies were performed in non-preconstricted arteries with either intact or removed endothelium using video microscopy. Results:In endothelium-intact ophthalmic arteries, mRNA for all five muscarinic receptor subtypes was detected, but M3 receptor mRNA was most abundant. In endothelium-removed ophthalmic arteries, M1, M2 and M3 receptors displayed similar mRNA expression levels, which were higher than those for M4 and M5 receptors. In functional studies, acetylcholine evoked vasoconstriction in endothelium-removed arteries from wild-type mice that was virtually abolished after incubation with the muscarinic receptor blocker atropine, indicative of the involvement of muscarinic receptors. In concentration-response experiments, acetylcholine and carbachol concentration-dependently constricted endothelium-removed ophthalmic arteries from wild-type mice, but produced only negligible responses in arteries from M3R-/- mice. In contrast, acetylcholine concentration-dependently dilated ophthalmic arteries with intact endothelium from wild-type mice, but not from M3R-/- mice. Responses to the nitric oxide donor nitroprusside and to KCl did not differ between ophthalmic arteries from wild-type and M3R-/- mice, neither in endothelium-intact nor in endothelium-removed arteries. Conclusions: These findings provide evidence that in murine ophthalmic arteries the muscarinic M3 receptor subtype mediates cholinergic endothelium-dependent vasodilation and endothelium-independent vasoconstriction.
    Investigative ophthalmology & visual science 01/2014; · 3.43 Impact Factor
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    ABSTRACT: Despite recent advances in crystallography and the availability of G-protein-coupled receptor (GPCR) structures, little is known about the mechanism of their activation process, as only the β2 adrenergic receptor (β2AR) and rhodopsin have been crystallized in fully active conformations. Here we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display. In addition to the expected changes in the intracellular surface, the structure reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the β2AR and rhodopsin. We also report the structure of the M2 receptor simultaneously bound to the orthosteric agonist iperoxo and the positive allosteric modulator LY2119620. This structure reveals that LY2119620 recognizes a largely pre-formed binding site in the extracellular vestibule of the iperoxo-bound receptor, inducing a slight contraction of this outer binding pocket. These structures offer important insights into the activation mechanism and allosteric modulation of muscarinic receptors.
    Nature 11/2013; · 38.60 Impact Factor
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    ABSTRACT: Rationale Asthma is a chronic obstructive airway disease, characterized by inflammation and remodeling. Acetylcholine contributes to symptoms by inducing bronchoconstriction via the muscarinic M3 receptor. Recent evidence suggests that bronchoconstriction can regulate airway remodeling and therefore implies a role for the muscarinic M3 receptor. Objectives To study the contribution of the muscarinic M3 receptor to allergen-induced remodeling using muscarinic M3 receptor subtype deficient (M3R(-/-)) mice. Wild-type, M1R(-/-) and M2R(-/-) mice were used as controls. Methods C57Bl/6 mice were sensitized and challenged with ovalbumin (twice weekly, for 4 weeks). Control animals were challenged with saline. Results Allergen exposure induced goblet cell metaplasia, airway smooth muscle thickening (1.7-fold), pulmonary vascular smooth muscle remodeling (1.5-fold) and deposition of collagen I (1.7-fold) and fibronectin (1.6-fold) in the airway wall of wild-type mice. These effects were absent or markedly lower in M3R(-/-) mice (30-100%), whereas M1R(-/-) and M2R(-/-) mice responded similar to wild-type mice. In addition, airway smooth muscle and pulmonary vascular smooth muscle mass were 35-40% lower in saline challenged M3R(-/-) mice compared to wild-type mice. Interestingly, allergen-induced airway inflammation, assessed as infiltrated eosinophils and Th2-cytokine expression, was similar or even enhanced in M3R(-/-) mice. Conclusions Our data indicate that acetylcholine contributes to allergen-induced remodeling and smooth muscle mass via the muscarinic M3 receptor, and not via M1 or M2 receptors. No stimulatory role for muscarinic M3 receptors in allergic inflammation was observed, suggesting that the role of acetylcholine in remodeling is independent of the allergic inflammatory response and may involve bronchoconstriction.
    American Journal of Respiratory Cell and Molecular Biology 10/2013; · 4.15 Impact Factor
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    ABSTRACT: Recent studies with M3 muscarinic acetylcholine receptor (M3R) mutant mice suggest that drugs selectively targeting this receptor subtype may prove useful for the treatment of various pathophysiological conditions. Moreover, the use of M3R-based designer G protein-coupled receptors (GPCRs) has provided novel insights into how Gq-coupled GPCRs can modulate whole-body glucose homeostasis by acting on specific peripheral cell types. More recently, we succeeded in using X-ray crystallography to determine the structure of the M3R bound to the bronchodilating drug tiotropium, a muscarinic antagonist (inverse agonist). This new structural information should facilitate the development of orthosteric or allosteric M3R-selective drugs that are predicted to have considerable therapeutic potential.
    Journal of Molecular Neuroscience 09/2013; · 2.89 Impact Factor
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    ABSTRACT: Increased hepatic glucose production is a key pathophysiological feature of type 2 diabetes. Like all other cell types, hepatocytes express many G protein-coupled receptors (GPCRs) that are linked to different functional classes of heterotrimeric G proteins. The important physiological functions mediated by Gs-coupled hepatic glucagon receptors are well-documented. In contrast, little is known about the in vivo physiological roles of hepatocyte GPCRs that are linked to G proteins of the Gq family. To address this issue, we established a transgenic mouse line (Hep-Rq mice) that expressed a Gq-linked designer receptor (Rq) in a hepatocyte-selective fashion. Importantly, Rq could no longer bind endogenous ligands but could be selectively activated by a synthetic drug, clozapine-N-oxide. Clozapine-N-oxide treatment of Hep-Rq mice enabled us to determine the metabolic consequences caused by selective activation of a Gq-coupled GPCR in hepatocytes in vivo. We found that acute Rq activation in vivo led to pronounced increases in blood glucose levels, resulting from increased rates of glycogen breakdown and gluconeogenesis. We also demonstrated that the expression of the V1b vasopressin receptor, a Gq-coupled receptor expressed by hepatocytes, was drastically increased in livers of ob/ob mice, a mouse model of diabetes. Strikingly, treatment of ob/ob mice with a selective V1b receptor antagonist led to reduced glucose excursions in a pyruvate challenge test. Taken together, these findings underscore the importance of Gq-coupled receptors in regulating hepatic glucose fluxes and suggest novel receptor targets for the treatment of type 2 diabetes.
    Endocrinology 07/2013; · 4.72 Impact Factor
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    ABSTRACT: The dorsal striatum has been implicated in reward-based decision making, but the role played by specific striatal circuits in these processes is essentially unknown. Using cell phenotype-specific viral vectors to express engineered G-protein-coupled DREADD (designer receptors exclusively activated by designer drugs) receptors, we enhanced Gi/o- or Gs-protein-mediated signaling selectively in direct-pathway (striatonigral) neurons of the dorsomedial striatum in Long-Evans rats during discrete periods of training of a high versus low reward-discrimination task. Surprisingly, these perturbations had no impact on reward preference, task performance, or improvement of performance during training. However, we found that transiently increasing Gi/o signaling during training significantly impaired the retention of task strategies used to maximize reward obtainment during subsequent preference testing, whereas increasing Gs signaling produced the opposite effect and significantly enhanced the encoding of a high-reward preference in this decision-making task. Thus, the fact that the endurance of this improved performance was significantly altered over time-long after these neurons were manipulated-indicates that it is under bidirectional control of canonical G-protein-mediated signaling in striatonigral neurons during training. These data demonstrate that cAMP-dependent signaling in direct-pathway neurons play a well-defined role in reward-related behavior; that is, they modulate the plasticity required for the retention of task-specific information that is used to improve performance on future renditions of the task.
    Journal of Neuroscience 07/2013; 33(28):11668-11676. · 6.91 Impact Factor
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    ABSTRACT: The release of insulin from pancreatic β-cells is regulated by a considerable number of G protein-coupled receptors (GPCRs). During the past several years, we have focused on the physiological importance of β-cell M3 muscarinic acetylcholine receptors (M3Rs). At the molecular level, the M3R selectively activates G proteins of the Gq family. Phenotypic analysis of several M3R mutant mouse models, including a mouse strain that lacks M3Rs only in pancreatic β-cells, indicated that β-cell M3Rs play a key role in maintaining blood glucose levels within a normal range. Additional studies with transgenic M3R mouse models strongly suggest that strategies aimed at enhancing signaling through β-cell M3Rs may prove useful in the treatment of type 2 diabetes. More recently, we analyzed transgenic mice that expressed an M3R-based designer receptor in a β-cell-specific fashion, which enabled us to chronically activate a β-cell Gq-coupled receptor by a drug that is otherwise pharmacologically inert. Drug-dependent activation of this designer receptor stimulated the sequential activation of Gq, PLC, ERK1/2, and IRS2 signaling, thus triggering a series of events that greatly improved β-cell function. Most importantly, chronic stimulation of this pathway protected mice against experimentally induced diabetes and glucose intolerance, either induced by streptozotocin or by the consumption of an energy-rich, high-fat diet. Since β-cells are endowed with numerous receptors that mediate their cellular effects via activation of Gq-type G proteins, these findings provide a rational basis for the development of novel antidiabetic drugs targeting this class of receptors.
    Molecular Endocrinology 07/2013; · 4.75 Impact Factor
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    ABSTRACT: Muscarinic receptor-based designer receptors have emerged as powerful novel tools to study G-protein-coupled receptor (GPCR) signaling and physiology. These new designer GPCRs, which are most frequently referred to as DREADDs (designer receptors exclusively activated by designer drug), are unable to bind acetylcholine, the endogenous muscarinic receptor agonist, but can be activated by clozapine-N-oxide (CNO), an otherwise pharmacologically inert compound, with high potency and efficacy. The various DREADDs differ primarily in their G protein coupling preference. More recently, an arrestin-biased DREADD has also been developed. The expression of DREADDs in distinct tissues or cell types has enabled researchers to study the outcome of selective stimulation of distinct GPCR (or arrestin) signaling pathways in a temporally and spatially controlled fashion in vivo. In this review, we provide an up-to-date snapshot of where this field currently stands and which important novel insights have been gained using this new technology.
    Trends in Pharmacological Sciences 06/2013; · 9.25 Impact Factor
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    Dataset: uterus MR
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    ABSTRACT: Type 2 diabetes (T2D) has emerged as a major threat to human health in most parts of the world. Therapeutic strategies aimed at improving pancreatic β cell function are predicted to prove beneficial for the treatment of T2D. In the present study, we demonstrate that drug-mediated, chronic, and selective activation of β cell Gq signaling greatly improve β cell function and glucose homeostasis in mice. These beneficial metabolic effects were accompanied by the enhanced expression of many genes critical for β cell function, maintenance, and differentiation. By employing a combination of in vivo and in vitro approaches, we identified a novel β cell pathway through which receptor-activated Gq leads to the sequential activation of ERK1/2 and IRS2 signaling, thus triggering a series of events that greatly improve β cell function. Importantly, we found that chronic stimulation of a designer Gq-coupled receptor selectively expressed in β cells prevented both streptozotocin-induced diabetes and the metabolic deficits associated with the consumption of a high-fat diet in mice. Since β cells are endowed with numerous receptors that mediate their cellular effects via activation of Gq-type G proteins, our findings provide a rational basis for the development of novel antidiabetic drugs targeting this class of receptors.
    The Journal of clinical investigation 03/2013; · 15.39 Impact Factor
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    ABSTRACT: Cholinergic tone contributes to airflow obstruction in COPD. Accordingly, anticholinergics are effective bronchodilators by blocking the muscarinic M3 receptor on airway smooth muscle. Recent evidence indicates that acetylcholine also contributes to airway inflammation. However, which muscarinic receptor subtype(s) regulate(s) this process is unknown.In this study, the contribution of the muscarinic M1, M2 and M3 receptor subtypes to cigarette smoke-induced airway inflammation was investigated by exposing muscarinic receptor subtype deficient mice to cigarette smoke for four days.In wild-type mice, cigarette smoke induced an increase in macrophages, neutrophils and lymphocytes in bronchoalveolar lavage fluid. Neutrophilic inflammation was higher in M1(-/-) and M2(-/-) mice compared to wild-type mice, but lower in M3(-/-) mice. Accordingly, the release of KC, MCP-1 and IL-6 was higher in M1(-/- )and M2(-/-) mice and reduced in M3(-/-) mice. Markers of remodeling were not increased after cigarette smoke exposure. However, M3(-/-) mice had reduced expression of TGF-β1 and matrix proteins. Cigarette smoke-induced inflammatory cell recruitment and KC release were also prevented by the M3-receptor selective antagonist 4-DAMP in wild-type mice.Collectively, our data indicate a pro-inflammatory role for the M3 receptor in cigarette smoke-induced neutrophilia and cytokine release, yet an anti-inflammatory role for M1 and M2 receptors.
    European Respiratory Journal 02/2013; · 6.36 Impact Factor
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    ABSTRACT: Impaired lung function caused by decreased airway diameter (bronchoconstriction) is frequently observed whether body weight is abnormally high or low. That these opposite conditions affect the airways similarly suggests that the regulation of airway diameter and body weight are intertwined. We show here that, independently of its regulation of appetite, melanocortin pathway, or sympathetic tone, leptin is necessary and sufficient to increase airway diameter by signaling through its cognate receptor in cholinergic neurons. The latter decreases parasympathetic signaling through the M(3) muscarinic receptor in airway smooth muscle cells, thereby increasing airway diameter without affecting local inflammation. Accordingly, decreasing parasympathetic tone genetically or pharmacologically corrects bronchoconstriction and normalizes lung function in obese mice regardless of bronchial inflammation. This study reveals an adipocyte-dependent regulation of bronchial diameter whose disruption contributes to the impaired lung function caused by abnormal body weight. These findings may be of use in the management of obesity-associated asthma.
    Cell metabolism 01/2013; 17(1):35-48. · 17.35 Impact Factor
  • Neuropsychopharmacology 12/2012; · 8.68 Impact Factor
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    ABSTRACT: Here, we describe a newly generated transgenic mouse in which the Gs DREADD (rM3Ds), an engineered G protein-coupled receptor, is selectively expressed in striatopallidal medium spiny neurons (MSNs). We first show that in vitro, rM3Ds can couple to Gα(olf) and induce cAMP accumulation in cultured neurons and HEK-T cells. The rM3Ds was then selectively and stably expressed in striatopallidal neurons by creating a transgenic mouse in which an adenosine2A (adora2a) receptor-containing bacterial artificial chromosome was employed to drive rM3Ds expression. In the adora2A-rM3Ds mouse, activation of rM3Ds by clozapine-N-oxide (CNO) induces DARPP-32 phosphorylation, consistent with the known consequence of activation of endogenous striatal Gα(s)-coupled GPCRs. We then tested whether CNO administration would produce behavioral responses associated with striatopallidal G(s) signaling and in this regard CNO dose-dependently decreases spontaneous locomotor activity and inhibits novelty induced locomotor activity. Lastly, we show that CNO prevented behavioral sensitization to amphetamine and increased AMPAR/NMDAR ratios in transgene-expressing neurons of the nucleus accumbens shell. These studies demonstrate the utility of adora2a-rM3Ds transgenic mice for the selective and non-invasive modulation of Gα(s) signaling in specific neuronal populations in vivo. This unique tool provides a new resource for elucidating the roles of striatopallidal MSN Gα(s) signaling in other neurobehavioral contexts.Neuropsychopharmacology accepted article preview online, 5 December 2012; doi:10.1038/npp.2012.251.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2012; · 8.68 Impact Factor

Publication Stats

8k Citations
1,418.08 Total Impact Points

Institutions

  • 1993–2014
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States
  • 2013
    • Stanford Medicine
      • Department of Molecular and Cellular Physiology
      Stanford, California, United States
  • 1989–2013
    • National Institutes of Health
      • • Laboratory of Bioorganic Chemistry (LBC)
      • • Laboratory of Molecular Biology
      Maryland, United States
  • 2012
    • Copenhagen University Hospital
      København, Capital Region, Denmark
  • 2011–2012
    • University of Copenhagen
      • Department of Neuroscience and Pharmacology
      København, Capital Region, Denmark
    • Johannes Gutenberg-Universität Mainz
      • Department of Pharmacology
      Mayence, Rheinland-Pfalz, Germany
    • University of Leicester
      • Department of Cell Physiology and Pharmacology
      Leicester, ENG, United Kingdom
  • 2005–2011
    • McLean Hospital
      • Alcohol and Drug Abuse Research Center
      Boston, MA, United States
    • Pennsylvania State University
      • Department of Anesthesiology
      University Park, MD, United States
  • 2010
    • Aston University
      Birmingham, England, United Kingdom
    • University of Maryland, Baltimore
      • Department of Medicine
      Baltimore, MD, United States
  • 2008–2010
    • University of Texas MD Anderson Cancer Center
      • Department of Anesthesiology and Perioperative Medicine
      Houston, TX, United States
  • 2009
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
      • Department of Ophthalmology
      Mainz, Rhineland-Palatinate, Germany
  • 2007–2009
    • Rakuno Gakuen University
      • Department of Veterinary Medicine
      Ebetsu, Hokkaido, Japan
  • 2005–2007
    • Gifu University
      • • Department of Pathogenetic Veterinary Science
      • • Department of Veterinary Medicine
      Gihu, Gifu, Japan
  • 2004
    • Technische Universität München
      • Department of Physiology
      München, Bavaria, Germany
    • Queen's University
      • Department of Physiology
      Kingston, Ontario, Canada
  • 2003–2004
    • University of California, Davis
      • Department of Dermatology
      Davis, CA, United States
    • Institut für Pharmakologie und Toxikologie der Bundeswehr
      München, Bavaria, Germany
  • 2002
    • National Institute of Child Health and Human Development
      Maryland, United States
  • 2001–2002
    • Eli Lilly
      • Neuroscience Research Division
      Indianapolis, Indiana, United States
    • University of Washington Seattle
      • Department of Physiology and Biophysics
      Seattle, WA, United States
    • Vanderbilt University
      • Center for Molecular Neuroscience
      Nashville, MI, United States
  • 1989–1996
    • National Institute of Mental Health (NIMH)
      Maryland, United States
  • 1992–1993
    • Roche Institute of Molecular Biology
      Nutley, New Jersey, United States
  • 1988–1991
    • University of Camerino
      • Dipartimento di Scienze Chimiche
      Matelica, The Marches, Italy
  • 1985–1989
    • Goethe-Universität Frankfurt am Main
      • • Faculty of Biochemistry, Chemistry and Pharmacy
      • • Pharmacological Institute for Scientists
      Frankfurt am Main, Hesse, Germany