Jürgen Wess, Ph.D. : NIDDK

Jürgen Wess, Ph.D.


LBC
MOLECULAR SIGNALLING SECTION
NIDDK, National Institutes of Health
Building 8A, Room B1A05
8 Center Dr.
Bethesda, MD 20892-0810
Tel: 301-402-3589
Fax: 301-480-3447
Email: jwess@helix.nih.gov

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 joined 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. More recently, Dr. Wess' laboratory has used gene targeting technology in mice to study the physiological and pathophysiological roles of a prototypical subfamily of GPCRs, the M1-M5 muscarinic acetylcholine 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 muscarinic acetylcholine receptor knockout mice

I. G protein-coupled receptors (GPCRs): Molecular basis of activation and function One major focus of my group is to understand how GPCR function at a molecular level. GPCRs form one of the largest protein families found in nature. GPCRs are cell surface receptors that mediate the functions of most neurotransmitters and hormones and also mediate vision, smell, and taste. Recent estimates are that the human genome contains ~800 distinct GPCR genes, corresponding to ~3-4% of all human genes. Strikingly, ~30% of drugs in current clinical use act on specific GPCRs. Understanding how GPCRs function at a molecular level is therefore of considerable practical relevance and may open new perspectives in the treatment of many diseases where the activation or inhibition of specific GPCR signalling pathways might be of therapeutic benefit. 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? Answers to these questions should eventually lead to novel therapeutic approaches aimed at inhibiting or stimulating the function of specific GPCRs. Techniques that will be applied for these studies include recombinant DNA technology (in vitro mutagenesis), expression of cloned receptors in cultured mammalian or yeast cells, receptor random mutagenesis, and characterization of the expressed receptors by a number of different techniques including radioligand binding studies, second messenger assays, and Western blotting analysis.

II. Generation and analysis of muscarinic acetylcholine receptor knockout 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 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 organs. We are currently studying different muscarinic receptor KO strains to learn more about the roles of the individual muscarinic receptors in the regulation of food intake and body weight and the pathophysiology of diabetes mellitus. We are also using different muscarinic receptor mutant mice to study the role of specific muscarinic receptors in important functions of the CNS such as learning and memory and drug-seeking behavior. These studies should provide a rational basis for the development of novel muscarinic drugs for the treatment of several important pathophysiological conditions including Alzheimer's disease, drug abuse, obesity, and diabetes.



Selected Publications:

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. Nat Chem Biol(4): 42-50, 2008. [Full Text/Abstract]

Vezys V, Masopust D, Desmarets M, Wess J, Zimring JC Analysis of CD8+ T cell-mediated anti-viral responses in mice with targeted deletions of the M1 or M5 muscarinic cholinergic receptors. Life Sci(80): 2330-3, 2007. [Full Text/Abstract]

Zhang HM, Zhou HY, Chen SR, Gautam D, Wess J, Pan HL Control of glycinergic input to spinal dorsal horn neurons by distinct muscarinic receptor subtypes revealed using knockout mice. J Pharmacol Exp Ther(323): 963-71, 2007. [Full Text/Abstract]

Thomsen M, Wörtwein G, Fink-Jensen A, Woldbye DP, Wess J, Caine SB Decreased prepulse inhibition and increased sensitivity to muscarinic, but not dopaminergic drugs in M5 muscarinic acetylcholine receptor knockout mice. Psychopharmacology (Berl)(192): 97-110, 2007. [Full Text/Abstract]

Lacroix C, Freeling J, Giles A, Wess J, Li YF Deficiency of M2 muscarinic acetylcholine receptors increases susceptibility of ventricular function to chronic adrenergic stress. Am J Physiol Heart Circ Physiol, 2007. [Full Text/Abstract]

Li JH, Han SJ, Hamdan FF, Kim SK, Jacobson KA, Bloodworth LM, Zhang X, Wess J Distinct structural changes in a G protein-coupled receptor caused by different classes of agonist ligands. J Biol Chem(282): 26284-93, 2007. [Full Text/Abstract]

Zarghooni S, Wunsch J, Bodenbenner M, Brüggmann D, Grando SA, Schwantes U, Wess J, Kummer W, Lips KS Expression of muscarinic and nicotinic acetylcholine receptors in the mouse urothelium. Life Sci(80): 2308-13, 2007. [Full Text/Abstract]

Kitazawa T, Hashiba K, Cao J, Unno T, Komori S, Yamada M, Wess J, Taneike T Functional roles of muscarinic M2 and M3 receptors in mouse stomach motility: studies with muscarinic receptor knockout mice. Eur J Pharmacol(554): 212-22, 2007. [Full Text/Abstract]

Scarselli M, Li B, Kim SK, Wess J Multiple residues in the second extracellular loop are critical for M3 muscarinic acetylcholine receptor activation. J Biol Chem(282): 7385-96, 2007. [Full Text/Abstract]

Wess J, Eglen RM, Gautam D Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nat Rev Drug Discov(6): 721-33, 2007. [Full Text/Abstract]

Kitazawa T, Hirama R, Masunaga K, Nakamura T, Asakawa K, Cao J, Teraoka H, Unno T, Komori SI, Yamada M, Wess J, Taneike T Muscarinic receptor subtypes involved in carbachol-induced contraction of mouse uterine smooth muscle. Naunyn Schmiedebergs Arch Pharmacol, 2007. [Full Text/Abstract]

Li B, Scarselli M, Knudsen CD, Kim SK, Jacobson KA, McMillin SM, Wess J Rapid identification of functionally critical amino acids in a G protein-coupled receptor. Nat Methods(4): 169-74, 2007. [Full Text/Abstract]

Gautam D, Han SJ, Duttaroy A, Mears D, Hamdan FF, Li JH, Cui Y, Jeon J, Wess J Role of the M3 muscarinic acetylcholine receptor in beta-cell function and glucose homeostasis. Diabetes Obes Metab(9 Suppl 2): 158-69, 2007. [Full Text/Abstract]

Sakamoto T, Unno T, Kitazawa T, Taneike T, Yamada M, Wess J, Nishimura M, Komori S Three distinct muscarinic signalling pathways for cationic channel activation in mouse gut smooth muscle cells. J Physiol(582): 41-61, 2007. [Full Text/Abstract]

Gautam D, Han SJ, Hamdan FF, Jeon J, Li B, Li JH, Cui Y, Mears D, Lu H, Deng C, Heard T, Wess J A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo. Cell Metab (3): 449-61, 2006. [Full Text/Abstract]

Gautam D, Gavrilova O, Jeon J, Pack S, Jou W, Cui Y, Li JH, Wess J Beneficial metabolic effects of M3 muscarinic acetylcholine receptor deficiency. Cell Metab (4): 363-75, 2006. [Full Text/Abstract]

Araya R, Noguchi T, Yuhki M, Kitamura N, Higuchi M, Saido TC, Seki K, Itohara S, Kawano M, Tanemura K, Takashima A, Yamada K, Kondoh Y, Kanno I, Wess J, Yamada M Loss of M5 muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice. Neurobiol Dis (24): 334-44, 2006. [Full Text/Abstract]

Gautam D, Duttaroy A, Cui Y, Han SJ, Deng C, Seeger T, Alzheimer C, Wess J M1-M3 muscarinic acetylcholine receptor-deficient mice: novel phenotypes. J Mol Neurosci (30): 157-60, 2006. [Full Text/Abstract]

Gautam D, Duttaroy A, Cui Y, Han SJ, Deng C, Seeger T, Alzheimer C, Wess J M1-M3 muscarinic acetylcholine receptor-deficient mice: novel phenotypes. J Mol Neurosci(30): 157-60, 2006. [Full Text/Abstract]

Origlia N, Kuczewski N, Aztiria E, Gautam D, Wess J, Domenici L Muscarinic acetylcholine receptor knockout mice show distinct synaptic plasticity impairments in the visual cortex. J Physiol (577): 829-40, 2006. [Full Text/Abstract]

Zhang HM, Chen SR, Matsui M, Gautam D, Wess J, Pan HL Opposing functions of spinal M2, M3, and M4 receptor subtypes in regulation of GABAergic inputs to dorsal horn neurons revealed by muscarinic receptor knockout mice. Mol Pharmacol (69): 1048-55, 2006. [Full Text/Abstract]

Kummer W, Wiegand S, Akinci S, Schinkel AH, Wess J, Koepsell H, Haberberger RV, Lips KS Role of acetylcholine and muscarinic receptors in serotonin-induced bronchoconstriction in the mouse. J Mol Neurosci (30): 67-8, 2006. [Full Text/Abstract]

Kummer W, Wiegand S, Akinci S, Schinkel AH, Wess J, Koepsell H, Haberberger RV, Lips KS Role of acetylcholine and muscarinic receptors in serotonin-induced bronchoconstriction in the mouse. J Mol Neurosci(30): 67-8, 2006. [Full Text/Abstract]

Kummer W, Wiegand S, Akinci S, Wessler I, Schinkel AH, Wess J, Koepsell H, Haberberger RV, Lips KS Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse. Respir Res (7): 65, 2006. [Full Text/Abstract]

Kummer W, Wiegand S, Akinci S, Wessler I, Schinkel AH, Wess J, Koepsell H, Haberberger RV, Lips KS Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse. Respir Res (7): 65, 2006. [Full Text/Abstract]

Unno T, Matsuyama H, Izumi Y, Yamada M, Wess J, Komori S Roles of M(2) and M(3) muscarinic receptors in cholinergic nerve-induced contractions in mouse ileum studied with receptor knockout mice. Br J Pharmacol (149): 1022-30, 2006. [Full Text/Abstract]

Allen IC, Hartney JM, Coffman TM, Penn RB, Wess J, Koller BH Thromboxane A2 induces airway constriction through an M3 muscarinic acetylcholine receptor-dependent mechanism. Am J Physiol Lung Cell Mol Physiol (290): L526-33, 2006. [Full Text/Abstract]

Ward SD, Hamdan FF, Bloodworth LM, Siddiqui NA, Li JH, Wess J Use of an in situ disulfide cross-linking strategy to study the dynamic properties of the cytoplasmic end of transmembrane domain VI of the M3 muscarinic acetylcholine receptor. Biochemistry (45): 676-85, 2006. [Full Text/Abstract]

Kuczewski N, Aztiria E, Gautam D, Wess J, Domenici L Acetylcholine modulates cortical synaptic transmission via different muscarinic receptors, as studied with receptor knockout mice. J Physiol (566): 907-19, 2005. [Full Text/Abstract]

Pfaff M, Powaga N, Akinci S, Schutz W, Banno Y, Wiegand S, Kummer W, Wess J, Haberberger RV Activation of the SPHK/S1P signalling pathway is coupled to muscarinic receptor-dependent regulation of peripheral airways. Respir Res (6): 48, 2005. [Full Text/Abstract]

Wess J Allosteric binding sites on muscarinic acetylcholine receptors. Mol Pharmacol (68): 1506-9, 2005. [Full Text/Abstract]

Xie G, Drachenberg C, Yamada M, Wess J, Raufman JP Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M1 and M3 muscarinic receptors. Am J Physiol Gastrointest Liver Physiol (289): G521-9, 2005. [Full Text/Abstract]

Gautam D, Han SJ, Heard TS, Cui Y, Miller G, Bloodworth L, Wess J Cholinergic stimulation of amylase secretion from pancreatic acinar cells studied with muscarinic acetylcholine receptor mutant mice. J Pharmacol Exp Ther (313): 995-1002, 2005. [Full Text/Abstract]

Khurana S, Yamada M, Wess J, Kennedy RH, Raufman JP Deoxycholyltaurine-induced vasodilation of rodent aorta is nitric oxide- and muscarinic M(3) receptor-dependent. Eur J Pharmacol (517): 103-10, 2005. [Full Text/Abstract]

Parnas H, Slutsky I, Rashkovan G, Silman I, Wess J, Parnas I Depolarization initiates phasic acetylcholine release by relief of a tonic block imposed by presynaptic M2 muscarinic receptors. J Neurophysiol (93): 3257-69, 2005. [Full Text/Abstract]

Trendelenburg AU, Meyer A, Wess J, Starke K Distinct mixtures of muscarinic receptor subtypes mediate inhibition of noradrenaline release in different mouse peripheral tissues, as studied with receptor knockout mice. Br J Pharmacol (145): 1153-9, 2005. [Full Text/Abstract]

Chen SR, Wess J, Pan HL Functional activity of the M2 and M4 receptor subtypes in the spinal cord studied with muscarinic acetylcholine receptor knockout mice. J Pharmacol Exp Ther (313): 765-70, 2005. [Full Text/Abstract]

Han SJ, Hamdan FF, Kim SK, Jacobson KA, Bloodworth LM, Li B, Wess J Identification of an agonist-induced conformational change occurring adjacent to the ligand-binding pocket of the M(3) muscarinic acetylcholine receptor. J Biol Chem (280): 34849-58, 2005. [Full Text/Abstract]

Unno T, Matsuyama H, Sakamoto T, Uchiyama M, Izumi Y, Okamoto H, Yamada M, Wess J, Komori S M(2) and M(3) muscarinic receptor-mediated contractions in longitudinal smooth muscle of the ileum studied with receptor knockout mice. Br J Pharmacol (146): 98-108, 2005. [Full Text/Abstract]

Goutagny R, Comte JC, Salvert D, Gomeza J, Yamada M, Wess J, Luppi PH, Fort P Paradoxical sleep in mice lacking M3 and M2/M4 muscarinic receptors. Neuropsychobiology (52): 140-6, 2005. [Full Text/Abstract]

Han SJ, Hamdan FF, Kim SK, Jacobson KA, Brichta L, Bloodworth LM, Li JH, Wess J Pronounced conformational changes following agonist activation of the M(3) muscarinic acetylcholine receptor. J Biol Chem (280): 24870-9, 2005. [Full Text/Abstract]

Li B, Nowak NM, Kim SK, Jacobson KA, Bagheri A, Schmidt C, Wess J Random mutagenesis of the M3 muscarinic acetylcholine receptor expressed in yeast: identification of second-site mutations that restore function to a coupling-deficient mutant M3 receptor. J Biol Chem (280): 5664-75, 2005. [Full Text/Abstract]

Thomsen M, Woldbye DP, Wortwein G, Fink-Jensen A, Wess J, Caine SB Reduced cocaine self-administration in muscarinic M5 acetylcholine receptor-deficient mice. J Neurosci (25): 8141-9, 2005. [Full Text/Abstract]

Zimring JC, Kapp LM, Yamada M, Wess J, Kapp JA Regulation of CD8+ cytolytic T lymphocyte differentiation by a cholinergic pathway. J Neuroimmunol (164): 66-75, 2005. [Full Text/Abstract]

Niebauer RT, Gao ZG, Li B, Wess J, Jacobson KA Signaling of the Human P2Y(1) Receptor Measured by a Yeast Growth Assay with Comparisons to Assays of Phospholipase C and Calcium Mobilization in 1321N1 Human Astrocytoma Cells. Purinergic Signal (1): 241-247, 2005. [Full Text/Abstract]

Niebauer RT, Gao ZG, Li B, Wess J, Jacobson KA Signaling of the Human P2Y(1) Receptor Measured by a Yeast Growth Assay with Comparisons to Assays of Phospholipase C and Calcium Mobilization in 1321N1 Human Astrocytoma Cells. Purinergic Signal (1): 241-247, 2005. [Full Text/Abstract]

Sangkuhl K, Schulz A, Rompler H, Yun J, Wess J, Schoneberg T Aminoglycoside-mediated rescue of a disease-causing nonsense mutation in the V2 vasopressin receptor gene in vitro and in vivo. Hum Mol Genet (13): 893-903, 2004. [Full Text/Abstract]

Gautam D, Heard TS, Cui Y, Miller G, Bloodworth L, Wess J Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and double-knockout mice. Mol Pharmacol (66): 260-7, 2004. [Full Text/Abstract]

Gautam D, Heard TS, Cui Y, Miller G, Bloodworth L, Wess J Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and double-knockout mice. Mol Pharmacol (66): 260-7, 2004. [Full Text/Abstract]

Fisher JT, Vincent SG, Gomeza J, Yamada M, Wess J Loss of vagally mediated bradycardia and bronchoconstriction in mice lacking M2 or M3 muscarinic acetylcholine receptors. FASEB J (18): 711-3, 2004. [Full Text/Abstract]



Page last updated: December 17, 2008

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