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。

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

http://www.columbia.edu/~col8/BuckAxel_ORcloning_Cell91.pdf

A novel multigene family may encode odorant receptors: A molecular basis for odor recognition

Background Controlled clinical trials have shown that beta-blockers can produce hemodynamic and symptomatic improvement in chronic heart failure, but the effect of these drugs on survival has not been determined. Methods We enrolled 1094 patients with chronic heart failure in a double-blind, placebo-controlled, stratified program, in which patients were assigned to one of four treatment protocols on the basis of their exercise capacity. Within each of the four protocols patients with mild, moderate, or severe heart failure with left ventricular ejection fractions ≤0.35 were randomly assigned to receive either placebo (n = 398) or the beta-blocker carvedilol (n = 696); background therapy with digoxin, diuretics, and an angiotensin-converting–enzyme inhibitor remained constant. Patients were observed for the occurrence of death or hospitalization for cardiovascular reasons during the following 6 months (12 months for the group with mild heart failure). Results The overall mortality rate was 7.8 percent in t...

The Effect of Carvedilol on Morbidity and Mortality in Patients With Chronic Heart Failure

Missale, Cristina, S. Russel Nash, Susan W. Robinson, Mohamed Jaber, and Marc G. Caron. Dopamine Receptors: From Structure to Function. Physiol. Rev. 78: 189–225, 1998. — The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1 and D5) couple to the G protein Gs and activate adenylyl cyclase. The other receptor subtypes belong to the D2-like subfamily (D2 , D3 , and D4) and are prototypic of G protein-coupled receptors that inhibit adenylyl cyclase and activate K+ channels. The genes for the D1 and D5 receptors are intronless, but pseudogenes of the D5 exist. The D2 and D3 receptors vary in certain tissues and species as a result of alternative splicing, and the human D4 receptor gene exhibits extensive polymorphic variation. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine s...

Dopamine Receptors: From Structure to Function

Authors Jan L. Brozek, MD, PhD – Department of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Canada Jean Bousquet, MD, PhD – Service des Maladies Respiratoires, Hopital Arnaud de Villeneuve, Montpellier, France, INSERM, CESP U1018, Respiratory and Environmental Epidemiology Team, France, and WHO Collaborating Center for Rhinitis and Asthma Carlos E. Baena-Cagnani, MD – Faculty of Medicine, Catholic University of Cordoba, Cordoba, Argentina Sergio Bonini, MD – Institute of Neurobiology and Molecular Medicine – CNR, Rome, Italy and Department of Medicine, Second University of Naples, Naples, Italy G. Walter Canonica, MD – Allergy & Respiratory Diseases, DIMI, Department of Internal Medicine, University of Genoa, Genoa, Italy Thomas B. Casale, MD – Division of Allergy and Immunology, Department of Medicine, Creighton University, Omaha, Nebraska, USA Roy Gerth van Wijk, MD, PhD – Section of Allergology, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands Ken Ohta, MD, PhD – Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan Torsten Zuberbier, MD – Department of Dermatology and Allergy, Charite Universitatsmedizin Berlin, Berlin, Germany Holger J. Schunemann, MD, PhD, MSc – Department of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Canada

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Allergic Rhinitis and Its Impact on Asthma

Activation of the G protein-coupled receptors by agonists may result in the activation of one or more G proteins, and in the recruitment of arrestins. The balance of activation of different pathways can be influenced by the ligand. Using BRET-based biosensors, we showed that the vasopressin V2 receptor activates or at least engages many different G proteins across all G protein subfamilies in response to its native agonist arginine vasopressin (AVP). This includes members of the Gi/o and G12/13 families that have not been previously reported. These signalling pathways are also activated by the synthetic peptide desmopressin and natural homologs of AVP, namely oxytocin and the non-mammalian hormone vasotocin. They demonstrated varying degrees of functional selectivity relative to AVP, as quantified using the operational model for quantifying ligand bias. Additionally, we modelled G protein activation as a Michaelis-Menten reaction. This approach provided a complementary way to quantify signalling bias, with an added benefit of clear separation of the effects of ligand affinity from the intrinsic activity of the receptor. These results showed that V2 receptor is not only promiscuous in its ability to engage several G proteins, but also that its signalling profile could be easily biased by small structural changes in the ligand.

/pdf/vasopressin-v2-is-a-promiscuous-g-protein-coupled-receptor-4skgi9vg6j.pdf

Vasopressin V2 is a promiscuous G protein-coupled receptor that is biased by its peptide ligands

> Bien que le concept de recepteurs membranaires date de la fin du XIXe et du debut du XXe siecle, avec les travaux de Ehrlich, Langley, Alhquist et d’autres [1], et que l’identification d’une sous-famille de recepteurs interagissant avec des proteines liant les nucleotides guanyles (proteines G) remonte aux annees 1960 [2], l’etude des recepteurs couples aux proteines G (RCPG) demeure plus actuelle que jamais. Les RCPG, qui sont la cible de plus de 30 % des medicaments prescrits, continuent de nous reveler de nouveaux aspects de leur mode de fonctionnement, ce qui laisse presager qu’ils seront, pour de nombreuses annees encore, des candidats de choix pour le developpement de nouveaux medicaments, plus actifs et adaptes a de nouvelles indications cliniques. Avec plus de 800 membres, les RCPG constituent la plus grande famille de proteines membranaires impliquees dans le transfert d’information de part et d’autre des membranes biologiques. Ils reconnaissent et traduisent l’information portee par une tres grande diversite de signaux, incluant la lumiere, des molecules odorantes, des ions, des acides amines, des amines biogenes, des lipides, des peptides et des glycoproteines. Acteurs centraux dans l’elaboration des reponses aux hormones et aux neurotransmetteurs, ils sont au cœur de processus aussi varies que la vision, l’olfaction, le gout, la croissance cellulaire, le chimiotactisme et l’entree cellulaire de certains virus et bacteries. Il n’est donc pas etonnant qu’ils aient ete, et demeurent, un sujet d’etude riche qui continue de fasciner de nombreux chercheurs. La representation classique des RCPG est celle de proteines a sept domaines transmembranaires qui, lorsqu’elles sont liees par leurs ligands respectifs, peuvent activer une proteine G heterotrimerique, laquelle, a son tour, module l’activite d’enzymes, de canaux, de transporteurs ou d’autres effecteurs, enclenchant ainsi une cascade de signalisation intracellulaire aboutissant a une reponse biologique. Les travaux realises au cours de ces dernieres annees, exploitant les outils de la biochimie, de la biologie moleculaire et cellulaire et, plus recemment, de la biologie structurale, ont permis d’affiner et dans certains cas de bouleverser nos idees recues au sujet des RCPG, avec des implications importantes pour le developpement de nouveaux medicaments.

/pdf/metaphores-nomenclature-et-nouveaux-paradigmes-de-1oklzp0wv8.pdf

Métaphores, nomenclature et nouveaux paradigmes de signalisation par les récepteurs couplés aux protéines G

Inverse agonists and g-protein-coupled receptors

Bioluminescence resonance energy transfer (BRET) is an energy transfer phenomenon from a luciferase donor to a fluorescence acceptor and serves as an indicator of protein-protein interaction or protein proximity. BRET imaging is a powerful tool in the investigation of signaling proteins because it enables spatial analysis of such protein interactions. Here, we describe a method exerting high-resolution BRET imaging by combining bright-light output luciferases, such as NanoLuc , photon-counting EM-CCD, and unique algorithms for image correction and denoising.

Michel Bouvier

Papers

Vasopressin V2 is a promiscuous G protein-coupled receptor that is biased by its peptide ligands

Métaphores, nomenclature et nouveaux paradigmes de signalisation par les récepteurs couplés aux protéines G

Inverse agonists and g-protein-coupled receptors

Bioluminescence Resonance Energy Transfer (BRET) Imaging in Living Cells: Image Acquisition and Quantification.

Transcriptome Analysis Reveals That G Protein-Coupled Receptors Are Potential Diagnostic Markers or Therapeutic Targets in Acute Myeloid Leukemia