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.

Resonating to the music of ubiquitination

Abstract: Beyond protein destruction: a new real-time assay to measure dynamic changes in ubiquitination promises to highlight the many other roles of this critical protein modification.

- βARK: β-Adrenergic receptor kinases (vertebrates)

Abstract: The chapter discusses the human b-adrenergic receptor kinases (bARK) along with its subunit and domain structure and the amino acid sequence of bARK. Desensitization is mediated in part by bARK-mediated phosphorylation of the receptor. b-Adrenergic receptor kinases, two isoforms of which are currently known (bARK-1 and -2), phosphorylate the agonist-occupied forms of several G protein-coupled receptors. Phosphorylation is thought to be followed by the binding of another protein, b-arrestin, which diminishes the functional coupling of the receptor to the G protein. This mechanism, thereby leads to homologous, or agonist-specific, desensitization. bARK activity is normally assayed as the agonist-dependent transfer of phosphate from [g32 P]ATP to purified, reconstituted b2AR. However, the light-dependent transfer of phosphate to urea-washed, rod outer segment membranes can also be utilized as an assay.

Biochemical and Molecular Characteristics of β-Adrenergic Receptor Binding Sites

Abstract: The availability of radiolabeled hormones, drugs and analogs which retain their characteristic biological activity and selectivity has provided a valuable tool for the study of the interaction of these agents with their target cell receptors. Despite the major advances in the investigation of receptors for polypeptide (14, 37) and steroid hormones (13) and nicotinic cholinergic drugs (11) using these techniques, the confident identification of the β-adrenergic receptors for catecholamines has remained until recently an elusive goal. Initial studies employed tritium labeled β-adrenergic agonists to identify binding sites in membrane fractions containing catecholamine-sensitive adenylate cyclase. However, some of the characteristics of binding observed with these agents diverged from which might be expected of the physiological β-adrenergic receptor (3, 17, 18). Perhaps the difficulties in these studies can be attributed to: 1) the multiple potential binding sites in addition to the adenylate cyclase coupled β-adrenergic receptor for labeled native catecholamines, 2) the relatively low affinity for cata-cholamines in in vitro membrane preparations (KD ≅ 10−6M), 3) the unimpressive specific radioactivity of available tritiated ligands (≅ 1 Ci/mmol), or 4) the absence of tissue preparations which provided a high concentration of β-adrenergic receptors relative to other constituents. Even in the case of the high affinity β-adrenergic antagonist propranolol, which would not likely interact with degradative enzymes and uptake mechanisms directed at catecholamines, binding characteristics indicated that this ligand binds disproportionately to non β-adrenergic receptor sites (40), possibly those responsible for the so-called “anaesthetic” properties of this drug.

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)