Robert J. Lefkowitz

Bio: Robert J. Lefkowitz is an academic researcher from Howard Hughes Medical Institute. The author has contributed to research in topics: Receptor & G protein-coupled receptor. The author has an hindex of 214, co-authored 860 publications receiving 147995 citations. Previous affiliations of Robert J. Lefkowitz include University of Nice Sophia Antipolis & University of Stuttgart.

Alfred Goodman Gilman (1941–2015)

Abstract: lfred Goodman Gilman discovered heterotrimeric G proteins, which help to usher chemical signals into cells. For this work, which reshaped our understanding of hormone and drug action, he shared the 1994 Nobel Prize in Medicine or Physiology with Martin Rodbell. Gilman's impact on biomedical research and education extended much further. He edited several editions of the definitive textbook The Pharmacological Basis of Therapeu-tics (or 'Goodman and Gilman'), which has served generations of medical and graduate students. in his words, a \" scientific silver spoon \" in his mouth. His father was the eminent pharmacologist Alfred Gilman Sr, who wrote the aforemen-tioned textbook with his close colleague Louis Goodman. Gilman Sr, in tribute to his friend, gave his son the middle name Goodman. As a child, young Gilman enjoyed trips to his father's labs at Columbia University and the Albert Einstein School of Medicine in New York. After completing a degree in biochemistry at Yale University in New Haven in 1962, he enrolled in one of the first MD–PhD programmes in the United States, at Case Western Reserve University in Cleveland, Ohio. The programme was run by Nobel laureate Earl Sutherland, the discoverer of cyclic AMP, a key intracellular messenger molecule. Here, Gilman solidified his interest in cell-signalling mechanisms.berg's lab, Gilman independently developed a sensitive technique for detecting cAMP that was immediately widely adopted. But it was his discovery of a family of G proteins made up of three different subu-nits (known as heterotrimeric G proteins) as a junior faculty member at the University of Virginia in Charlottesville, that transformed the field of cell signalling. In the 1970s, evidence was mounting that the hormone receptors involved in cell signalling were independent entities in the plasma membrane. Gilman and his postdoc Elliott Ross were investigating this problem using membranes from a lymphoma cell line called cyc –. These cells seemed to lack the key enzyme adenylyl cyclase, which cataly-ses formation of cAMP. The cells retained the β-adrenergic receptor that binds a class of molecules called catecholamines, which includes the hormone adrenaline. This binding stimulates adenylyl cyclase, increasing the formation of cAMP. To these cyc – membranes, Gilman and Ross added an extract of another cell line, mouse L cells, which retained enzyme activity but lacked the hormone receptors. To their delight, this 'reconstitution' system worked and yielded hormone-sensitive adenylyl cyclase activity. However, control experiments indicated that extracts in which the cyclase activity …

System and method for homogenous gpcr phosphorylation and identification of beta-2 adrenergic receptor positive allosteric modulators

Abstract: The disclosure is directed to a G-protein coupled receptor complex. The complex includes (i) a chimeric G protein-coupled receptor (GPCR) comprising a non-native amino acid sequence located within the C-terminus of the GPCR and a synthetic phosphopeptide ligated to the non-native amino acid sequence; and (ii) a β-arrestin (βarr) protein bound to the C-terminus of the GPCR. The disclosure also provides an in vitro method for producing the aforementioned complex, as well as methods for identifying compounds or ligands which bind to and modulate the activity of the complex. Positive allosteric modulators of the β2 adrenergic receptor identified by screening a DNA-encoded library potentiate the activity of β2 agonists and have application in the treatment of obstructive airway disease, bronchospasm, or pre-term labor.

INHIBITION OF βARK AND β-ARRESTIN

Abstract: β-adrenergic receptor kinase (βARK) and β-arrestin function in the homologous or agonist-activated desensitization of G-protein coupled receptors. Both βARK-2 and β-arrestin-2 isoforms are highly enriched in and localized to the cilia and dendritic knobs of the olfactory receptor neurons where the initial events of olfactory signal transduction occur as well as being localized to spermatids. Administration of neutralizing antibodies to βARK-2 and β-arrestin-2 enhances the response to odorants and attenuates desensitization.

Modeles de trafic modifies pour l'arrestine et les recepteurs couples a la proteine g par l'intermediaire d'une chimere d'arrestine-ubiquitine

Abstract: La presente invention concerne une arrestine modifiee comprenant une molecule d'arrestine et une molecule d'ubiquitine. Cette arrestine modifiee presente une affinite accrue pour un GPCR, et se deplace avec ce GPCR dans des endosomes. La presente invention concerne en outre une methode de criblage de composes et de solutions d'echantillon en vue de l'identification d'un agoniste, d'un antagoniste ou d'un agoniste inverse du GPCR, ou d'un compose actif de desensibilisation. L'arrestine modifiee est utile dans les methodes de la presente invention.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans

Abstract: Experimental introduction of RNA into cells can be used in certain biological systems to interfere with the function of an endogenous gene Such effects have been proposed to result from a simple antisense mechanism that depends on hybridization between the injected RNA and endogenous messenger RNA transcripts RNA interference has been used in the nematode Caenorhabditis elegans to manipulate gene expression Here we investigate the requirements for structure and delivery of the interfering RNA To our surprise, we found that double-stranded RNA was substantially more effective at producing interference than was either strand individually After injection into adult animals, purified single strands had at most a modest effect, whereas double-stranded mixtures caused potent and specific interference The effects of this interference were evident in both the injected animals and their progeny Only a few molecules of injected double-stranded RNA were required per affected cell, arguing against stochiometric interference with endogenous mRNA and suggesting that there could be a catalytic or amplification component in the interference process

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

Abstract: The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)