A5015095365- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Neuroscience and Neuropharmacology Research
- Pancreatic function and diabetes
- Nicotinic Acetylcholine Receptors Study
- Ion channel regulation and function
- Adipose Tissue and Metabolism
- Diabetes Treatment and Management
- Monoclonal and Polyclonal Antibodies Research
- Protein Kinase Regulation and GTPase Signaling
- Neurotransmitter Receptor Influence on Behavior
- Adenosine and Purinergic Signaling
- Asthma and respiratory diseases
- Neuroendocrine regulation and behavior
- Lipid Membrane Structure and Behavior
- Regulation of Appetite and Obesity
- Nitric Oxide and Endothelin Effects
- Ion Transport and Channel Regulation
- Biochemical Analysis and Sensing Techniques
- Electrolyte and hormonal disorders
- Adipokines, Inflammation, and Metabolic Diseases
- Metabolism, Diabetes, and Cancer
- Neuroscience of respiration and sleep
- Pain Mechanisms and Treatments
- Ion Channels and Receptors
National Institute of Diabetes and Digestive and Kidney Diseases
2016-2025
National Institutes of Health
2015-2024
Toxicologie, Pharmacologie et Signalisation Cellulaire
2005-2017
Institute of Bioorganic Chemistry
2001-2016
University of California, San Francisco
1996-2013
Stanford University
2013
Friedrich-Alexander-Universität Erlangen-Nürnberg
2013
University of Toronto
2013
Howard Hughes Medical Institute
2010
Duke University Hospital
2010
G-protein-coupled receptors (GPCRs) play fundamental roles in regulating the activity of virtually every body cell. Upon binding extracellular ligands, GPCRs interact with a specific subset heterotrimeric G-proteins that can then, their activated forms, inhibit or activate various effector enzymes and/or ion channels. Molecular cloning studies have shown form one largest protein families found nature, and it is estimated approximately 1000 different such exist mammals. The molecular...
G protein-independent, arrestin-dependent signaling is a paradigm that broadens the scope of protein-coupled receptors (GPCRs) beyond proteins for numerous biological processes. However, arrestin in collective absence functional has never been demonstrated. Here we achieve state "zero G" at cellular level using HEK293 cells depleted by CRISPR/Cas9 technology Gs/q/12 families Gα proteins, along with pertussis toxin-mediated inactivation Gi/o. Together lacking β-arrestins ("zero arrestin"),...
Impaired functioning of pancreatic β cells is a key hallmark type 2 diabetes. cell function modulated by the actions different classes heterotrimeric G proteins. The functional consequences activating specific protein signaling pathways in vivo are not well understood at present, primarily due to fact that protein-coupled receptors (GPCRs) also expressed many other tissues. To circumvent these difficulties, we developed chemical-genetic approach allows for conditional and selective...
Increased secretion of growth hormone leads to gigantism in children and acromegaly adults; the genetic causes are poorly understood.We performed clinical studies samples obtained from 43 patients with then sequenced an implicated gene 248 acromegaly.We observed microduplication on chromosome Xq26.3 13 gigantism; these samples, 4 were members two unrelated kindreds, 9 sporadic cases. All had disease onset during early childhood. Of who did not carry microduplication, none presented before...
Demyelination in MS disrupts nerve signals and contributes to axon degeneration. While remyelination promises restore lost function, it remains unclear whether will prevent axonal loss. Inflammatory demyelination is accompanied by significant neuronal loss the experimental autoimmune encephalomyelitis (EAE) mouse model evidence for this complicated ongoing inflammation, degeneration possible remyelination. Demonstrating functional significance of necessitates selectively altering timing...
Members of the muscarinic acetylcholine receptor family are thought to play key roles in regulation a large number important functions CNS. However, precise individual subtypes modulating these processes not well understood at present, primarily because lack ligands with sufficient subtype selectivity. To investigate behavioral significance M(1) (M(1)R), which is abundantly expressed forebrain, we subjected receptor-deficient mice (M(1)R(-/-) mice) battery tests. M(1)R(-/-) showed no...
Members of the muscarinic acetylcholine receptor family (M1-M5) are known to be involved in a great number important central and peripheral physiological pathophysiological processes. Because overlapping expression patterns M1-M5 subtypes lack ligands endowed with sufficient subtype selectivity, precise functions individual remain elucidated. To explore roles M2 receptor, we have generated mice lacking functional receptors by using targeted mutagenesis mouse embryonic stem cells. The...
We have tested the hypothesis that guanine-nucleotide-binding-protein-coupled receptors may be able to interact with each other at a molecular level. To address this question, we initially created two chimeric receptors, alpha 2/m3 and m3/alpha 2, in which C-terminal receptor portions (containing transmembrane domains VI VII) were exchanged between 2C-adrenergic m3 muscarinic receptor. Transfection of COS-7 cells either constructs alone did not result any detectable binding activity for...
Forebrain muscarinic acetylcholine (ACh) receptors (mAChRs; M1-M5) are predicted to play important roles in many fundamental central functions, including higher cognitive processes and modulation of extrapyramidal motor activity. Synaptic ACh levels known be regulated by the activity presynaptic autoreceptors mediating inhibition release. Primarily because use ligands with limited receptor subtype selectivity, classical pharmacological studies have led conflicting results regarding identity...
Muscarinic acetylcholine receptors (M(1)-M(5)) regulate many key functions of the central and peripheral nervous system. Primarily because lack receptor subtype-selective ligands, precise physiological roles individual muscarinic subtypes remain to be elucidated. Interestingly, M(4) subtype is expressed abundantly in striatum various other forebrain regions. To study its potential role regulation locomotor activity functions, we used gene-targeting technology create mice that functional...
The M 5 muscarinic receptor is the most recent member of acetylcholine family (M 1 -M ) to be cloned. At present, physiological relevance this subtype remains unknown, primarily because its low expression levels and lack receptor-selective ligands. To circumvent these difficulties, we used gene targeting technology generate receptor-deficient mice ( M5R −/− mice). did not differ from their wild-type littermates in various behavioral pharmacologic tests. However, vitro neurotransmitter...
Several studies suggest, but do not prove directly, that muscarinic receptors may be able to form dimeric or oligomeric arrays. To address this issue in a more direct fashion, we designed series of biochemical experiments using modified version the rat m3 receptor (referred as m3′) model system. When membrane lysates prepared from m3′ receptor-expressing COS-7 cells were subjected Western blot analysis under non-reducing conditions, several immunoreactive species observed corresponding size...