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.

Myocardial beta-adrenergic receptors from adrenalectomized rats: impaired formation of high-affinity agonist-receptor complexes.

Abstract: Adrenal steroid hormones potentiate beta-adrenergic actions on the heart. Accordingly, we investigated the effects of adrenalectomy on agonist and antagonist interactions with myocardial beta-adrenergic receptors and adenylate cyclase. The affinity and number of beta-adrenergic receptor sites, both defined by the antagonist (-) [3H]dihydroalprenolol, did not change after adrenalectomy. Computer modelling of agonist (-)-isoproterenol competition curves indicated the presence of two discrete receptor states with high and low affinities. After adrenalectomy, the agonist curves were shifted to the right, and the dissociation constant of the high-affinity state significantly rose from 12 to 48 nM (p < .001), but the dissociation constant of the low affinity state was unchanged. Although basal, maximal isoproterenol-stimulated and fluoride-stimulated adenylate cyclase activities were unaltered, the EC50 for isoproterenol stimulation was increased significantly from 490 to 1500 nM (p <.018). These results suggest that adrenal steroid hormones may regulate the ability of the beta-adrenergic receptors to form a high-affinity "coupled" state, presumably by modulating the interaction of the receptor with nucleotide regulatory proteins.

Localization of the fourth membrane spanning domain as a ligand binding site in the human platelet alpha 2-adrenergic receptor.

Abstract: The human platelet {alpha}{sub 2}-adrenergic receptor is an integral membrane protein which binds epinephrine. The gene for this receptor has been cloned, and the primary structure is thus known. A model of its secondary structure predicts that the receptor has seven transmembrane spanning domains. By covalent labeling and peptide mapping, the authors have identified a region of the receptor that is directly involved with ligand binding. Partially purified preparations of the receptor were covalently radiolabeled with either of two specific photoaffinity ligands: ({sup 3}H)SKF 102229 (an antagonist) or p-azido({sup 3}H)clonidine (an agonist). The radiolabeled receptors were then digested with specific endopeptidases, and peptides containing the covalently bound radioligands were identified. Lysylendopeptidase treatment of ({sup 3}H)SKF 102229 labeled receptor yielded one peptide of M{sub r} 2400 as the product of a complete digest. Endopeptidase Arg-C gave a labeled peptide of M{sub r} 4000, which was further digested to the M{sub r} 2400 peptide by additional treatment with lysylendopeptidase. Using p-azido({sup 3}H)clonidine-labeled receptor, a similar M{sub r} 2400 peptide was obtained by lysylendopeptidase cleavage. This M{sub r} 2400 peptide corresponds to the fourth transmembrane spanning domain of the receptor. These data suggest that this region forms part of the ligand binding domainmore » of the human platelet {alpha}{sub 2}-adrenergic receptor.« less

Clinical physiology of adrenergic receptor regulation

Abstract: Radioligand binding studies now permit the direct investigation of the alpha- and beta-adrenergic receptors. The concentration of the receptors in cell membranes is modulated by a wide variety of physiological and pathophysiological variables and may be either increased or decreased in different conditions. Ligand binding techniques have also shed light on the ways in which the adrenergic receptors are coupled to other components of the hormone-sensitive adenylate cyclase system. This “coupling” is also a highly regulated step, control of which importantly influences catecholamine and sensitivity of tissues.

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)