Differential binding of ligands to the apolipoprotein E receptor 2

Apolipoprotein E receptor 2 (apoER2) is an important participant in the Reelin signaling pathway that directs cell positioning during embryogenesis. ApoER2 is a cell surface molecule that elicits intracellular signal transduction through binding of Reelin. The structural requirements for Reelin binding to apoER2 and the receptor domains involved in this process are unclear at present. Using a series of receptor mutants, we characterized the interaction of apoER2 with Reelin and compared this interaction to that of apoER2 with the receptor-associated protein (RAP), an apoER2 ligand that does not induce signaling. By surface plasmon resonance we demonstrate that apoER2 exhibits 6-fold higher affinity for Reelin than the very low density lipoprotein receptor (VLDLR), which also functions as a Reelin receptor (KD 0.2 nM versus KD 1.2 nM). Acidic amino acid residues in complement-type repeat domains 1 and 3 of apoER2 are required for Reelin binding. The same regions of the receptor are also bound by RAP with a 25-fold lower affinity (KD 5 nM). Whereas RAP binds to apoER2 with a 1:1 stoichiometry, experimental evidence suggests that Reelin associates with two or more receptor molecules simultaneously to achieve high-affinity interaction. This finding indicates that aggregation of apoER2 by multivalent ligands such as Reelin may be the structural basis for signal transduction

Prognostic Value of Nonischemic Ringlike Left Ventricular Scar in Patients with Apparently Idiopathic Nonsustained Ventricular Arrhythmias

none24Background: Left ventricular (LV) scar on late gadolinium enhancement (LGE) cardiac magnetic resonance has been correlated with life-threatening arrhythmic events in patients with apparently idiopathic ventricular arrhythmias (VAs). We investigated the prognostic significance of a specific LV-LGE phenotype characterized by a ringlike pattern of fibrosis. Methods: A total of 686 patients with apparently idiopathic nonsustained VA underwent contrast-enhanced cardiac magnetic resonance. A ringlike pattern of LV scar was defined as LV subepicardial/midmyocardial LGE involving at least 3 contiguous segments in the same short-axis slice. The end point of the study was time to the composite outcome of all-cause death, resuscitated cardiac arrest because of ventricular fibrillation or hemodynamically unstable ventricular tachycardia and appropriate implantable cardioverter defibrillator therapy. Results: A total of 28 patients (4%) had a ringlike pattern of scar (group A), 78 (11%) had a non-ringlike pattern (group B), and 580 (85%) had normal cardiac magnetic resonance with no LGE (group C). Group A patients were younger compared with groups B and C (median age, 40 vs 52 vs 45 years; P<0.01), more frequently men (96% vs 82% vs 55%; P<0.01), with a higher prevalence of family history of sudden cardiac death or cardiomyopathy (39% vs 14% vs 6%; P<0.01) and more frequent history of unexplained syncope (18% vs 9% vs 3%; P<0.01). All patients in group A showed VA with a right bundle-branch block morphology versus 69% in group B and 21% in group C (P<0.01). Multifocal VAs were observed in 46% of group A patients compared with 26% of group B and 4% of group C (P<0.01). After a median follow-up of 61 months (range, 34-84 months), the composite outcome occurred in 14 patients (50.0%) in group A versus 15 (19.0%) in group B and 2 (0.3%) in group C (P<0.01). After multivariable adjustment, the presence of LGE with ringlike pattern remained independently associated with increased risk of the composite end point (hazard ratio, 68.98 [95% CI, 14.67-324.39], P<0.01). Conclusions: In patients with apparently idiopathic nonsustained VA, nonischemic LV scar with a ringlike pattern is associated with malignant arrhythmic events.noneMuser D.; Nucifora G.; Muser D.; Nucifora G.; Pieroni M.; Castro S.A.; Casado Arroyo R.; Maeda S.; Benhayon D.A.; Liuba I.; Sadek M.; Magnani S.; Enriquez A.; Liang J.J.; Sassone B.; Desjardins B.; Dixit S.; Deo R.; Garcia F.C.; Callans D.J.; Frankel D.S.; Selvanayagam J.B.; Marchlinski F.E.; Santangeli P.Muser, D.; Nucifora, G.; Muser, D.; Nucifora, G.; Pieroni, M.; Castro, S. A.; Casado Arroyo, R.; Maeda, S.; Benhayon, D. A.; Liuba, I.; Sadek, M.; Magnani, S.; Enriquez, A.; Liang, J. J.; Sassone, B.; Desjardins, B.; Dixit, S.; Deo, R.; Garcia, F. C.; Callans, D. J.; Frankel, D. S.; Selvanayagam, J. B.; Marchlinski, F. E.; Santangeli, P

Alternative splicing modulates Disabled-1 (Dab1) function in the developing chick retina

The Reelin–Disabled 1 (Dab1)-signaling pathway plays a critical role in neuronal cell positioning in the brain. We have isolated two alternatively spliced variants of Dab1 from chick retina, an early form (chDab1-E) expressed in undifferentiated cells and a late form (chDab1-L) expressed in amacrine and ganglion cells. A key difference between the two forms is the exclusion in chDab1-E of two Src-related tyrosine kinase recognition sites implicated in Reelin-mediated Dab1 tyrosine phosphorylation. Retinal cultures transfected with a chDab1-L expression construct undergo a dramatic change in morphology, accompanied by the formation of numerous thin elongated processes, increased tyrosine phosphorylation, activation of Src family kinase(s) and increased levels of the axonal outgrowth protein growth-associated protein-43. In contrast, chDab1-E transfectants retain an undifferentiated morphology. Mutational analysis implicates a specific tyrosine (tyr-198) in the morphological and biochemical alterations associated with chDab1-L expression. We propose that alternative splicing of chDab1 represents an effective and flexible way of regulating the Reelin–Dab1-signaling pathway in a mixed cell population, by ensuring that secreted Reelin activates the signaling cascade only in target neuronal cells

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on arrhythmias and cognitive function: what is the best practice?

Publicado também em: https://repositorio.unifesp.br/handle/11600/55712Developed in partnership with and endorsed by the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC), the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS) and the Latin American Heart Rhythm Society (LAHRS). This article has been co-published with permission in EP Europace, HeartRhythm, and Journal of Arrhythmia The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style Either citation can be used when citing this article. For copies of this document, please contact the Elsevier Inc. Reprint Department ([email protected]). Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the Heart Rhythm Society.Heart Ctr Leipzig, Dept Electrophysiol, Strumpellstr 39, D-04289 Leipzig, GermanyTaipei Vet Gen Hosp, Taipei, TaiwanHosp Israelita Albert Einstein, Sao Paulo, BrazilCtr Privado Cardiol, San Miguel De Tucuman, ArgentinaCardiac & Vasc Inst, Mem Hlth, Hollywood, FL USABoston Univ, Sch Med, Framingham Heart Study, Boston, MA 02118 USABoston Univ, Sch Publ Hlth, Framingham Heart Study, Boston, MA 02118 USAIntermt Med Ctr, Murray, UT USAUniv Minnesota, Dept Med, Cardiovasc Div, Minneapolis, MN USAUniv Fed Sao Paulo, Sch Med, Sao Paulo, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Sao Paulo, BrazilUniv Franc Rabelais, Ctr Hosp Univ Trousseau, Serv Cardiol, Tours, FranceSt Vincenz Hosp Paderborn, Dept Cardiol & Intens Care Med, Working Grp, Magdeburg, GermanyUniv Hosp Magdeburg, Mol Electrophysiol, Magdeburg, GermanyUniv Melbourne, Royal Melbourne Hosp, Melbourne, Vic, AustraliaKings Coll London, London, EnglandKorea Univ, Ctr Med, Seoul, South KoreaUniv Birmingham, Inst Cardiovasc Sci, Birmingham, W Midlands, EnglandAalborg Univ, Dept Clin Med, Aalborg Thrombosis Res Unit, Aalborg, DenmarkMassachusetts Gen Hosp, Boston, MA 02114 USAInst Nacl Cardiol, Dept Electrocardiog, Mexico City, DF, MexicoUniv Belgrade, Sch Med, Belgrade, SerbiaClin Ctr Serbia, Cardiol Clin, Belgrade, SerbiaInst Cardiol Corrientes, Corrientes, ArgentinaSt Georges Univ London, Mol & Clin Sci Res Inst, Cardiol Clin Acad Grp, London, EnglandNatl Heart Ctr, Singapore, SingaporeUniv Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R ChinaSouthlake Reg Hlth Ctr, Newmarket, ON, CanadaBeijing Fuwai Hosp, Beijing, Peoples R ChinaCleveland Clin, Cleveland, OH USAUniv Fed Sao Paulo, Sch Med, Sao Paulo, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Sao Paulo, BrazilWeb of Scienc