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.

Anti–β1-adrenergic receptor antibodies and heart failure: causation, not just correlation

Abstract: Do anti–β-adrenergic receptor (anti–β-AR) antibodies play a role in the pathogenesis of chronic systolic heart failure (CHF)? This question emerged almost 30 years ago (1), when antibodies with β-adrenergic stimulating (agonist) activity were discovered in the serum of patients with Chagas disease, one of the most common causes of CHF worldwide (2). Since that time, IgGs with agonist activity for the β1-adrenergic receptor (β1-AR) have been found in sera not only from patients with Chagas disease, but also from patients with idiopathic dilated cardiomyopathy (3) as well as ischemic (4) cardiomyopathy. Whether these antibodies merely correlate with myocardial inflammation that leads to CHF, result from myocardial inflammation, or actually contribute to the pathogenesis of CHF could not be ascertained — until now. In this issue of the JCI, Jahns et al. employed isogenic injections of anti–β1-AR antiserum in inbred rats to produce a cardiomyopathy that appears to be non-inflammatory (5). In so doing, these authors conclusively demonstrated that agonistic, anti–β1-AR IgG — by itself — is sufficient to engender the sort of myocardial dysfunction characteristic of CHF. This finding fundamentally advances our understanding of CHF. However, it should not really surprise us, because it represents a logical extension of diverse but congruent investigations conducted over several decades. To provide historical and mechanistic perspectives for the elegant work of Jahns et al., we address several questions that relate their work to contemporary concepts of β1-AR pathophysiology: How might IgG activate the β1-AR, and how could chronic β1-AR activation result in cardiomyocyte toxicity? What molecular mechanisms regulate the β1-AR when it is chronically stimulated by IgG or other agonists, and how might these mechanisms affect the pathogenesis of CHF? Lastly, how can these perspectives elucidate the therapeutic efficacy of β-AR antagonists, or “beta blockers,” in CHF?

Differential regulation of the alpha 2-adrenergic receptor by Na+ and guanine nucleotides

Abstract: Many hormones interact with receptors which stimulate the enzyme adenylate cyclase. Less well characterized ar those receptors which mediate an inhibition of adenylate cyclase activity. However, guanine nucleotides are clearly important in the regulation of both stimulatory and inhibitory receptors. Monovalent cations, notably Na+, regulate many inhibitory receptor systems but apparently not stimulatory receptors. We investigate here the effects of Na+ and guanine nucleotides on the adenylate cyclase-coupled inhibitory alpha 2-adrenergic receptor of the rabbit platelet. Computer modelling of adrenaline competition curves with 3H-dihydroergocryptine (3H-DHE) indicates that adrenaline induces two distinct affinity states of the alpha 2 receptor--one of higher (alpha 2H) and the other of lower (alpha 2L) affinity. Guanyl-5'-yl-imidodiphosphate (Gpp(NH)p) seems to reduce adrenaline affinity to converting the high-affinity state into the low-affinity form of the receptor. In contrast, Na+ reduces adrenaline affinity at both the high- and low-affinity states of the alpha 2 receptor while preserving receptor heterogeneity. Thus, guanine nucleotides and Na+ differ in the manner by which each reduces agonist affinity for the alpha 2-adrenergic receptor.

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)