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.

Augmentation of Cardiac Contractility Mediated by the Human β3-Adrenergic Receptor Overexpressed in the Hearts of Transgenic Mice

Abstract: Background Stimulation of β1- and β2-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the β3AR is also expressed in the human heart and that its stimulation leads to negative inotropic effects. Methods and Results To better understand the role of β3ARs in cardiac function, we generated transgenic mice with cardiac-specific overexpression of 330 fmol/mg protein of the human β3AR (TGβ3 mice). Hemodynamic characterization was performed by cardiac catheterization in closed-chest anesthetized mice, by pressure-volume-loop analysis, and by echocardiography in conscious mice. After propranolol blockade of endogenous β1- and β2ARs, isoproterenol resulted in an increase in contractility in the TGβ3 mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human β3AR agonist L-755,507 significantly increased contractility in the TGβ3 mice (160%), with no effect in wild-type mice, as determined by hemodynamic measurements and b...

Interactions of agonists with platelet alpha 2-adrenergic receptors.

Abstract: Epinephrine induces human platelet aggregation by interacting with alpha-adrenergic receptors. These sites were demonstrated by radioligand-binding techniques using the new antagonist ligand, [3H]yohimbine. The sites labeled by [3H]yohimbine had the specificity of alpha 2-receptors with the affinity of yohimbine much greater than prazosin. Epinephrine-mediated inhibition of prostaglandin E1-stimulated adenylate cyclase activity in human platelet lysates was also found to have an alpha 2-receptor specificity. Competition curves of antagonists with [3H]yohimbine indicated a homogeneous population of alpha 2-receptors. In contrast, competition curves of a series of full and partial agonists with [3H]yohimbine were resolved into two distinct affinity states; the ratio of the dissociation constants of agonists for the low and high affinity states was positively correlated with the agonist's intrinsic activity for inhibition of adenylate cyclase. Guanine nucleotides were found to destabilize the high affinity form of the alpha 2-receptors. At high nucleotide concentrations, all high affinity states of the receptor were converted to the low affinity form. The formation of the high affinity agonist-binding state may reflect an interaction between the agonist-receptor complex and an additional membrane component, and probably reflects events involved in alpha 2-receptor-adenylate cyclase coupling.

Saving the Endangered Physician-Scientist - A Plan for Accelerating Medical Breakthroughs.

Abstract: Saving the Endangered Physician-Scientist Physician-scientists have been a driving force in biomedical research and have made broad contributions in both the private and public sectors. In the past...

Ras-dependent activation of fibroblast mitogen-activated protein kinase by 5-HT1A receptor via a G protein beta gamma-subunit-initiated pathway.

Abstract: Serotonin (5-HT) is a potent mitogen in many cells types, an action which is frequently mediated through pertussis toxin-sensitive G proteins. In the current study, we used pharmacological inhibitors and dominant negative signaling constructs to delineate elements which participate in the activation of MAPK, a growth-associated mitogen-activated protein kinase, by human G protein-coupled 5-HT1A receptor transfected into CHO-K1 cells in a stable manner. The activation pathway does not directly involve phorbol ester-sensitive protein kinase C types, but does require (i) pertussis toxin-sensitive G protein beta gamma-subunits, (ii) a staurosporine- and genistein-sensitive protein kinase, (iii) phosphoinositide-3'-kinase activity, (iv) activation of Sos in a multimolecular complex that contains p46Shc, and p52Shc, and Grb2, (v) the GTPase p21Ras, and (vi) the protein kinase p74Raf-1. These data demonstrate that the 5-HT1A receptor mediates MAPK activity by convergence upon a common activation pathway that is shared with receptor tyrosine kinases.

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)