Jürgen Wess, Ph.D.
LBC
MOLECULAR SIGNALLING SECTION
NIDDK, National Institutes of Health
Building 8A
, Room B1A05
8 Center Dr.
Bethesda, MD 20814
Tel: 301-402-3589
Fax: 301-480-3447
Email: jwess@helix.nih.gov
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Education / Previous Training and Experience:
Dr. Wess received his Ph. D. in Pharmacology from the Johann Wolfgang-Goethe University in Frankfurt/Main (Germany) in 1987. From 1988-1991, he worked at the National Institutes of Health (NIH; joint appointment at NIMH/NINDS) in Bethesda, Maryland, USA, as a postdoctoral fellow. From 1991 to 1997, he was heading the 'G Protein-Coupled Receptor Unit', first at NIH-NINDS (1991-1993) and then at NIH-NIDDK (1993-1997). In 1998, Dr. Wess was appointed Chief of the 'Molecular Signaling Section' in the Laboratory of Bioorganic Chemistry, NIH-NIDDK. One major goal of Dr. Wess' research is to understand how G protein-coupled receptors (GPCRs) function at the molecular level. Moreover, Dr. Wess' laboratory is using genetically engineered mice to study the physiological and pathophysiological roles of various GPCRs, including the M1-M5 muscarinic acetylcholine and the V2 vasopressin receptors.
Research Statement:
My laboratory focuses on the following two lines of work:
I. G protein-coupled receptors (GPCRs): Molecular basis of activation and function
II. Generation and analysis of GPCR mutant mice
I. G PROTEIN-COUPLED RECEPTORS (GPCRs): MOLECULAR BASIS OF ACTIVATION AND FUNCTION
One major focus of my group is to understand how GPCRs function at the molecular level. GPCRs, one of the largest protein families found in nature, are cell surface receptors that mediate the functions of an extraordinarily large number of extracellular ligands (neurotransmitters, hormones, etc.). The human genome contains ~800 distinct GPCR genes, corresponding to ~3-4% of all human genes. Strikingly, ~30-40% of drugs in current clinical use act on specific GPCRs. Understanding how GPCRs function at the molecular level is therefore of considerable therapeutic relevance. My lab uses different molecular genetic and biochemical strategies to address the following fundamental questions regarding the structure and function of these receptors: 1. How to GPCRs recognize and activate G proteins? 2. Which conformational changes do activating ligands induce in the receptor protein? To address these questions, we are using disulfide-cross linking approaches, receptor random mutagenesis, and yeast expression technology, besides several other techniques. These studies should eventually lead to novel therapeutic approaches aimed at modulating the function of specific GPCRs.
II. GENERATION AND ANALYSIS OF GPCR MUTANT MICE
Many of the important physiological functions of the neurotransmitter acetylcholine are caused by the interaction of acetylcholine with a group of GPCRs referred to as muscarinic receptors. Molecular cloning studies have revealed the existence of five molecularly distinct muscarinic receptor subtypes which are referred to as M1-M5. The M1-M5 receptors are abundantly expressed in most cells and tissues and are known to be critically involved in the regulation of a great number of fundamental physiological processes including, for example, the regulation of body weight and food intake, the release of insulin from pancreatic beta cells, and a larger number of important functions of the central nervous system (CNS) including most cognitive processes. At present, it remains unclear in most cases which specific muscarinic receptor subtypes are involved in mediating the diverse muscarinic actions of acetylcholine. To elucidate the physiological roles of the individual muscarinic receptor subtypes, we are using gene targeting techniques, including Cre/loxP technology, to generate mouse lines lacking functional M1-M5 muscarinic receptors either throughout the body or only in certain tissues or cell types. Current phenotyping studies are focusing on the potential roles of the different muscarinic receptor subtypes in regulating energy and glucose homeostasis in various peripheral and central tissues.
In a related line of work, we are generating and analyzing transgenic mice expressing mutationally modified mutant GPCRs in specific, metabolically relevant cell types such pancreatic beta-cells, hepatocytes, myocytes, and certain subsets of hypothalamic neurons. In the system that we are employing, distinct G protein signaling pathways can selectively activated in vivo in a cell type-specific and conditional fashion, involving the administration of a drug that selectively activates the transgenically expressed mutant GPCRs. These studies, which are being carried out in collaboration with the NIDDK metabolic phenotyping, transgenic, and mouse knockout core facilities, are likely to identify novel therapeutic targets for the treatment of various pathophysiological conditions including type 2 diabetes and obesity.
X-linked nephrogenic diabetes insipidus (XNDI) is a severe kidney disease caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene, resulting in the loss of renal urine-concentrating ability. We recently generated the first viable mouse model of XNDI in which the V2R gene can be conditionally deleted in adult mice. These newly generated V2R mutant mice are currently being used as an animal model to identify new drugs useful for the treatment of XNDI.
Selected Publications:
Hu J, Wang Y, Zhang X, Lloyd JR, Li JH, Karpiak J, Costanzi S, Wess J. Structural basis of G protein-coupled receptor-G protein interactions. Nat. Chem. Biol., May 30, 2010 [Epub ahead of print]
Ruiz de Azua I, Scarselli M, Rosemond E, Gautam D, Jou W, Gavrilova O, Ebert PJ, Levitt P, Wess J. RGS4 is a negative regulator of insulin release from pancreatic beta-cells in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 107, 7999-8004, 2010
Jeon J, Dencker D, Wörtwein G, Woldbye DP, Cui Y, Davis AA, Levey AI, Schütz G, Sager TN, Mørk A, Li C, Deng CX, Fink-Jensen A, Wess J. A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors. J. Neurosci. 30, 2396-2405, 2010
Guettier JM, Gautam D, Scarselli M, Ruiz de Azua I, Li JH, Rosemond E, Ma X, Gonzalez FJ, Armbruster BN, Lu H, Roth BL, Wess J. A chemical-genetic approach to study G protein regulation of beta-cell function in vivo. Proc. Natl. Acad. Sci. U.S.A. 106, 19197-19202, 2009
Li JH, Chou CL, Li B, Gavrilova O, Eisner C, Schnermann J, Anderson SA, Deng CX, Knepper MA, Wess J. A selective EP4 PGE2 receptor agonist alleviates disease in a new mouse model of X-linked nephrogenic diabetes insipidus. J. Clin. Invest. 119, 3115-3126, 2009
Gautam D, Jeon J, Starost MF, Han SJ, Hamdan FF, Cui Y, Parlow AF, Gavrilova O, Szalayova I, Mezey E, Wess J. Neuronal M3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth. Proc. Natl. Acad. Sci. USA 106, 6398-6403, 2009
Wess J, Han SJ, Kim SK, Jacobson KA, Li JH. Conformational changes involved in G-protein-coupled-receptor activation. Trends Pharmacol. Sci. 29, 616-625, 2008.
Conklin BR, Hsiao EC, Claeysen S, Dumuis A, Srinivasan S, Forsayeth JR, Guettier JM, Chang WC, Pei Y, McCarthy KD, Nissenson RA, Wess J, Bockaert J, Roth BL. Engineering GPCR signaling pathways with RASSLs. Nature Methods 5, 673-678, 2008.
Shirey JK, Xiang Z, Orton D, Brady AE, Johnson KA, Williams R, Ayala JE, Rodriguez AL, Wess J, Weaver D, Niswender CM, Conn PJ. An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission. Nature Chem. Biol. 4, 42-50, 2008.
Wess, J., Eglen, R.M., and Gautam, D. Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development Nat. Revs. Drug Discov. 6, 721-733, 2007.
Li, B., Scarselli, M., Knudsen, C.D., Kim, S.K., Jacobson, K.A., McMillin, S.M., and Wess, J. Rapid identification of functionally critical amino acids in a G protein-coupled receptor. Nature Methods 4, 169-174, 2007.
Gautam, D., Gavrilova, O., Jeon, J., Pack, S., Jou, W., Cui, Y., Li, J.H., and Wess, J. Beneficial metabolic effects of M3 muscarinic acetylcholine receptor deficiency. Cell Metabolism 4, 363-75, 2006.
Gautam, D., Han, S.J., Hamdan, F.F., Jeon, J., Li, B., Li, J.H., Cui, Y., Mears, D., Lu, H., Deng, C., Heard, T., and Wess, J. A critical role for b cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo. Cell Metabolism 3, 449-61, 2006.
T. Seeger, I. Fedorova, F. Zheng, T. Miyakawa, E. Koustova, J. Gomeza, A. S. Basile, C. Alzheimer, and J. Wess. M2 Muscarinic acetylcholine receptor knockout mice show deficits in behavioral flexibility, working memory, and hippocampal plasticity. J. Neurosci. 24, 10117-10127, 2004.
A. Duttaroy, C. L. Zimliki, D. Gautam, Y. Cui, D. Mears, and J. Wess. Muscarinic stimulation of pancreatic insulin and glucagon release is abolished in M3 muscarinic acetylcholine receptor-deficient mice, Diabetes 53, 1714-1720, 2004.
J. T. Fisher, S. G. Vincent, J. Gomeza, M. Yamada, and J. Wess. Loss of vagally-mediated bradycardia and bronchoconstriction in mice lacking M2 or M3 muscarinic acetylcholine receptors. FASEB J. 18, 711-713, 2004.
J. Wess. Muscarinic acetylcholine receptor knockout mice: novel phenotypes and clinical implications. Annu. Rev. Pharmacol. Toxicol. 44, 423-450, 2004.
A. Fisahn, M. Yamada, A. Duttaroy, J.-W. Gan, C.-X. Deng, C. J. McBain and J. Wess. Muscarinic induction of hippocampal gamma oscillations requires coupling of the M1 receptor to two mixed cation channels. Neuron 33, 615-624, 2002.
A. S. Basile, I. Fedorova, A. Zapata, X. Liu, T. Shippenberg, A. Duttaroy, M. Yamada and J. Wess. Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal, but not morphine analgesia Proc. Natl. Acad. Sci. USA 99, 11452-11457, 2002.
M. Yamada, T. Miyakawa, A. Duttaroy, A. Yamanaka, T. Moriguchi, R. Makita, M. Ogawa, C. J. Chou, B. Xia, J. N. Crawley, C. C. Felder, C. Deng and J. Wess. Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean. Nature 410, 207-212, 2001.
M. Yamada, K. G. Lamping, A. Duttaroy, W. Zhang, Y. Cui, F. P. Bymaster, D. L. McKinzie, C. C. Felder, C. X. Deng, F. M. Faraci and J. Wess. Cholinergic dilation of cerebral blood vessels is abolished in M5 muscarinic acetylcholine receptor knockout mice. Proc. Natl. Acad. Sci. USA 98, 14096-14101, 2001.
J. Yun, T. Schöneberg, J. Liu, A. Schulz, C. A. Ecelbarger, D. Promeneur, S. Nielsen, H. Sheng, A. Grinberg, C. Deng and J. Wess. Generation and phenotype of mouse strains harboring a nonsense mutation within the V2 vasopressin receptor coding sequence. J. Clin. Invest. 106, 1361-1371, 2000.
J. Gomeza, H. Shannon, E. Kostenis, C. Felder, L. Zhang, J. Brodkin, A. Grinberg, H. Sheng and J. Wess. Pronounced pharmacologic deficits in M2 muscarinic acetylcholine receptor knockout mice. Proc. Natl. Acad. Sci. USA 96, 1692-1697, 1999.
J. Gomeza, L. Zhang, E. Kostenis, C. Felder, F. Bymaster, J. Brodkin, H. Shannon, B. Xia, C. Deng and J. Wess. Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M4 muscarinic acetylcholine receptor knockout mice. Proc. Natl. Acad. Sci. USA 96, 10483-104888, 1999.
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