Defective interactions of protein partner with ion channels and transporters as alternative mechanisms of membrane channelopathies

The past twenty years have revealed the existence of numerous ion channel mutations resulting in human pathology. Ion channels provide the basis of diverse cellular functions, ranging from hormone secretion, excitation–contraction coupling, cell signaling, immune response, and trans-epithelial transport. Therefore, the regulation of biophysical properties of channels is vital in human physiology. Only within the last decade has the role of non-ion channel components come to light in regard to ion channel spatial, temporal, and biophysical regulation in physiology. A growing number of auxiliary components have been determined to play elemental roles in excitable cell physiology, with dysfunction resulting in disorders and related manifestations. This review focuses on the broad implications of such dysfunction, focusing on disease-causing mutations that alter interactions between ion channels and auxiliary ion channel components in a diverse set of human excitable cell disease. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé     

Magnesium gating of cardiac gap junction channels

We aimed to study kinetics of modulation by intracellular Mg²⁺ of cardiac gap junction (Mg²⁺ gate). Paired myocytes of guinea-pig ventricle were superfused with solutions containing various concentrations of Mg²⁺. In order to rapidly apply Mg²⁺ to one aspect of the gap junction, the non-junctional membrane of one of the pair was perforated at nearly the connecting site by pulses of nitrogen laser beam. The gap junction conductance (G_j) was measured by clamping the membrane potential of the other cell using two-electrode voltage clamp method. The laser perforation immediately increased G_j, followed by slow G_j change with time constant of 3.5 s at 10 mM Mg²⁺. Mg²⁺ more than 1.0 mM attenuated dose-dependently the gap junction conductance and lower Mg²⁺ (0.6 mM) increased G_j with a Hill coefficient of 3.4 and a half-maximum effective concentration of 0.6 mM. The time course of G_j changes was fitted by single exponential function, and the relationship between the reciprocal of time constant and Mg²⁺ concentration was almost linear. Based on the experimental data, a mathematical model of Mg²⁺ gate with one open state and three closed states well reproduced experimental results. One-dimensional cable model of thirty ventricular myocytes connected to the Mg²⁺ gate model suggested a pivotal role of the Mg²⁺ gate of gap junction under pathological conditions.     

Mutations in VEGFA are associated with congenital left ventricular outflow tract obstruction

Left ventricular outflow tract obstruction (LVOTO) comprises a spectrum of stenotic lesions. Previous studies have shown that the vascular endothelial growth factor (VEGF) signaling system plays a critical role in cardiac cushion formation, vasculogenesis, and angiogenesis. We hypothesize that VEGFA may be a potential candidate gene associated with the spectrum of LVOTO lesions. However, it remains unclear whether the VEGFA gene is responsible for the development of LVOTO malformations. In this study, we identified three exon mutations in the VEGFA gene in three of 192 nonsyndromic LVOTO patients, and the overall mutation frequency was 1.6% (3/192). The c.454C>T (p.Arg152X) nonsense mutation and c.19_22dupGACA (p.Thr8ArgfsX78) internal tandem duplication mutation each introduced a premature stop codon and are predicted to produce a truncated VEGFA protein. The c.998G>A missense mutation changes a highly conserved arginine to a glutamine at residue 333 (p.Arg333Gln). These mutations were carried by some family members, and average penetrance was 33.3%. The present study suggests, for the first time to our knowledge, that VEGFA mutations may be associated with congenital LVOTO malformations. We provide evidence that LVOTO is likely oligogenic.     

步长稳心颗粒治疗136例心律失常的临床疗效观察

目的:观察步长稳心颗粒对心律失常的治疗效果。方法:将心律失常患者136例随机分成两组,治疗组68例用稳心颗粒治疗,对照组68例用胺碘酮治疗,治疗4周观察静息心电图、动态心电图、Q-T离散度,平均心室率,不良反应的变化。结果:治疗4周后,治疗组总有效率优于对照组,差异有统计学意义(P<0.05)。治疗组治疗后Q-T离散度减小,差异有统计学意义(P<0.05);对照组胺碘酮治疗后Q-T离散度变化不大。治疗组和对照组治疗后平均心室率均下降,差异有统计学意义(P<0.05),但两组间平均心室率比较差异无统计学意义(P>0.05);治疗组不良反应发生率明显低于对照组(P<0.05)。结论:稳心颗粒能有效治疗心律失常,毒副作用小,安全可靠。     

The in vitro chronotropic and inotropic effects of vasoactive intestinal peptide (VIP) on the atria and ventricular papillary muscle from Cynomolgus monkey heart

The in vitro chronotropic and inotropic effects of vasoactive intestinal peptide (VIP) and of isoproterenol, two agents known to stimulate cardiac adenylate cyclase were compared on the heart from Cynomolgus monkey using the spontaneously beating right atrium, the electrically stimulated left atrium, and the electrically-stimulated ventricular papillary muscle. VIP increased concentration-dependently the rate of beating of the right atrium as well as the contractility of both atria but its efficiency was lower than that of D,L-isoproterenol. VIP also stimulated concentration-dependently, and this time as efficiently as D,L-isoproterenol, the contractility of papillary muscle. These VIP effects were unaltered by the neuronal blocker tetrodotoxin. In addition, the moderate inhibition exerted by the beta-adrenergic blocker D,L-propranolol on VIP effects argued against the implication of beta-adrenergic receptors in VIP effects. These results indicate that VIP exerts a direct stimulatory influence on the rate and contractility of Cynomolgus monkey heart.     

Gender-dependent effects of selenite on the perfused rat heart

Gender differences are related to the manner in which the heart responds to chronic and acute stress conditions of physiological and pathological nature. Depending on dose, sodium selenite acts as an antioxidant proven to have beneficial effects in several pathological conditions G. Drasch, J. Schopfer, and G. N. Schrauzer, Selenium/cadmium ratios in human prostates: indicators of prostate cancer risk of smokers and non-smokers, and relevance to the cancer protective effects of selenium,Biol. Trace Element Res. 103(2), 103–107 (2005); R. G. Kasseroller and G. N. Schrauzer, Treatment of secondary lymphedema of the arm with physical decongestive therapy and sodium selenite: a review,Am. J. Ther. 7(4), 273–279 (2000); G. N. Schrauzer, Anticarcinogenic effects of selenium,Cell. Mol. Life Sci. 57(13–14), 1864–1873 (2000); I. S. Palmer and O. E. Olson, Relative toxicities of selenite and selenate in the drinking water of rats,J. Nutr. 104(3), 306–314 (1974). To date, little is known about the gender-dependent direct effects of toxic doses of selenite on electrophysiology of the cardiovascular system H. A. Schroeder and M. Mitchener, Selenium and tellurium in rats: effect on growth, survival and tumors,J. Nutr. 101(11), 1531–1540 (1971); G. N. Schrauzer, The nutritional significance, metabolism and toxicology of selenomethionine,Adv. Food Nutr. Res. 47, 73–112 (2003). In the present study, the effects of in vitro toxic concentrations of sodium selenite ranging from 10^-6 M to 10^-3 M were tested on both male and female rat heart preparations. The toxic effects seen in an electrocardiogram and left ventricular pressure were dose and sex dependent at most of the tested concentrations. The present study clearly shows that at toxic doses, stress conditions are induced by selenite, resulting in gender-dependent modifications of the heart function. This modification is more pronounced in the contraction cascade of female rats. Males, on the other hand, had been much more affected in excitation-related parameters.     

Role of cardiovascular nitric oxide system in C-type natriuretic peptide effects

The aims were to evaluate the role of cardiovascular nitric oxide (NO)-system in C-type natriuretic peptide (CNP) actions and to investigate receptor types and signaling pathways involved in this interaction. Wistar rats were infused with saline or CNP. Mean arterial pressure (MAP) and nitrites and nitrates (NOx) excretion were determined. NO synthase (NOS) activity and NOS expression (Western blot) were analyzed in atria, ventricle and aorta. CNP decreased MAP and increased NOx excretion. CNP estimulated NOS activity, inducing no changes on cardiac and vascular endothelial NOS expression. NOS activity induced by CNP was abolished by suramin and calmidazoliumand but it is not modified by anantin. CNP would interact with NPR-C receptor coupled via G proteins leading to the activation Ca(2+)-calmodulin dependent endothelial NOS, increasing NO production which would induce the reduction in cardiac myocyte contractility and ANP synthesis and secretion in right atria and the relaxation of vascular smooth muscle.     

超声检测左心室舒张功能的临床意义——85例超声检测结果与冠状动脉造影的对照分析

目的超声心动图检测左心室舒张功能与冠状动脉造影对照分析,探讨超声诊断的临床意义。方法85例临床疑诊冠心病超声检查左心室二尖瓣口舒张早、晚期血流充盈速度E、A两峰峰值,计算E/A比值,其结果分为舒张功能正常和降低两组。全部病人均与冠状动脉造影结果对照分析。结果超声检测左心室舒张功能与冠脉造影均正常24例,均异常53例,共77例,符合率90.59%,不符合8例,占9.41%;本文依据冠脉造影提出超声检测左心室舒张功能正常值;并发现冠心病早期舒张功能降低,且随年龄与病程长短不同。结论超声检测左心室舒张功能的改变与冠脉造影符合率高,舒张功能于冠心病早期可降低,随病程长短不同,为临床对冠心病诊治和预防提供有价值的信息。     

Differential distribution of the endoplasmic reticulum network in filamentous fungi

Filamentous fungi are composed of hyphal compartments divided by septa, which communicate via septal pores. Apical compartments can elongate to over 100 microm without septum formation and possess a polarized distribution of organelles. In Aspergillus, subapical compartments are arrested in interphase but can reinitiate mitosis and growth by branching. Recent reports using green fluorescent protein (GFP) technology have demonstrated the highly differentiated localization of the endoplasmic reticulum (ER) network in various regions of the hyphae: the gradient distribution from the apical region, the localization along the septum, differential distributions in adjacent compartments, and the dynamic morphological change during septum formation. In this review the spatial regulation of the ER network in multicellular filamentous fungi is discussed.