324 research outputs found
Predicting the Impact of Sex-specific Differences in Vascular Smooth Muscle Cells in Mechanisms of Hypertension
No full textHypertension is considered to be the largest modifiable risk factor for cardiovascular disease. Even with the longstanding recognition of hypertension as a disease, there is still poor understanding of the observable differences in men and women responses to antihypertensive agents. The necessity of treating hypertension to prevent premature death has led to the urgent need to develop new approaches for revealing sex-specific mechanisms of hypertension and predicting how drugs will alter vascular function. The smooth muscle cells that line the walls of small resistance arteries and arterioles have been the subject of investigation for decades due to their important role in regulating blood flow and blood pressure. This dissertation focuses on formulating an in silico model of the vascular smooth muscle cell incorporating new electrophysiological and Ca2+ signaling data suggesting key sex-specific differences in male and female arterial myocytes. The model highlights the importance of sex-specific differences in Cav1.2 and Kv2.1 channels. The Cav1.2 and Kv2.1 channels have previously been associated with remodeling in the pathogenesis of hypertension and model predictions described herein also suggest differential responses to antihypertensive agents. The work covered in this dissertation provides insights into sex-specific differences in arterial smooth muscle cell physiology and has the potential to expand our understanding for how sex-dependent differences in the expression, spatial organization, and function of key important ion channels are involved in the regulation of vascular smooth muscle
Role of Membrane Microdomains in Compartmentation of cAMP Signaling
No full textSpatially restricting cAMP production to discrete subcellular locations permits selective regulation of specific functional responses. But exactly where and how cAMP signaling is confined is not fully understood. Different receptors and adenylyl cyclase isoforms responsible for cAMP production are not uniformly distributed between lipid raft and non-lipid raft domains of the plasma membrane. We sought to determine the role that these membrane domains play in organizing cAMP responses in HEK293 cells. The freely diffusible FRET-based biosensor Epac2-camps was used to measure global cAMP responses, while versions of the probe targeted to lipid raft (Epac2-MyrPalm) and non-raft (Epac2-CAAX) domains were used to monitor local cAMP production near the plasma membrane. Disruption of lipid rafts by cholesterol depletion selectively altered cAMP responses produced by raft-associated receptors. The results indicate that receptors associated with lipid raft as well as non-lipid raft domains can contribute to global cAMP responses. In addition, basal cAMP activity was found to be significantly higher in non-raft domains. This was supported by the fact that pharmacologic inhibition of adenylyl cyclase activity reduced basal cAMP activity detected by Epac2-CAAX but not Epac2-MyrPalm or Epac2-camps. Responses detected by Epac2-CAAX were also more sensitive to direct stimulation of adenylyl cyclase activity, but less sensitive to inhibition of phosphodiesterase activity. Quantitative modeling was used to demonstrate that differences in adenylyl cyclase and phosphodiesterase activities are necessary but not sufficient to explain compartmentation of cAMP associated with different microdomains of the plasma membrane
Ionic mechanisms of endogenous bursting in CA3 hippocampal pyramidal neurons: a model study.
No full textA critical property of some neurons is burst firing, which in the hippocampus plays a primary role in reliable transmission of electrical signals. However, bursting may also contribute to synchronization of electrical activity in networks of neurons, a hallmark of epilepsy. Understanding the ionic mechanisms of bursting in a single neuron, and how mutations associated with epilepsy modify these mechanisms, is an important building block for understanding the emergent network behaviors. We present a single-compartment model of a CA3 hippocampal pyramidal neuron based on recent experimental data. We then use the model to determine the roles of primary depolarizing currents in burst generation. The single compartment model incorporates accurate representations of sodium (Na(+)) channels (Na(V)1.1) and T-type calcium (Ca(2+)) channel subtypes (Ca(V)3.1, Ca(V)3.2, and Ca(V)3.3). Our simulations predict the importance of Na(+) and T-type Ca(2+) channels in hippocampal pyramidal cell bursting and reveal the distinct contribution of each subtype to burst morphology. We also performed fast-slow analysis in a reduced comparable model, which shows that our model burst is generated as a result of the interaction of two slow variables, the T-type Ca(2+) channel activation gate and the Ca(2+)-dependent potassium (K(+)) channel activation gate. The model reproduces a range of experimentally observed phenomena including afterdepolarizing potentials, spike widening at the end of the burst, and rebound. Finally, we use the model to simulate the effects of two epilepsy-linked mutations: R1648H in Na(V)1.1 and C456S in Ca(V)3.2, both of which result in increased cellular excitability
Predictive Computational Models Of Complex Biological Systems: Antiarrhythmics And Cardiac Tissue Dynamics
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Parameterization for In-Silico Modeling of Ion Channel Interactions with Drugs.
No full textSince the first Hodgkin and Huxley ion channel model was described in the 1950s, there has been an explosion in mathematical models to describe ion channel function. As experimental data has become richer, models have concomitantly been improved to better represent ion channel kinetic processes, although these improvements have generally resulted in more model complexity and an increase in the number of parameters necessary to populate the models. Models have also been developed to explicitly model drug interactions with ion channels. Recent models of drug-channel interactions account for the discrete kinetics of drug interaction with distinct ion channel state conformations, as it has become clear that such interactions underlie complex emergent kinetics such as use-dependent block. Here, we describe an approach for developing a model for ion channel drug interactions. The method describes the process of extracting rate constants from experimental electrophysiological function data to use as initial conditions for the model parameters. We then describe implementation of a parameter optimization method to refine the model rate constants describing ion channel drug kinetics. The algorithm takes advantage of readily available parallel computing tools to speed up the optimization. Finally, we describe some potential applications of the platform including the potential for gaining fundamental mechanistic insights into ion channel function and applications to in silico drug screening and development
A National Heart, Lung, and Blood Institute and Office of Rare Diseases Workshop Consensus Report About the Diagnosis, Phenotyping, Molecular Mechanisms, and Therapeutic Approaches for Primary Cardiomyopathies of Gene Mutations Affecting Ion Channel Function
No full textThe National Heart, Lung, and Blood Institute and Office of Rare Diseases at the National Institutes of Health organized a workshop (September 14 to 15, 2006, in Bethesda, Md) to advise on new research directions needed for improved identification and treatment of rare inherited arrhythmias. These included the following: (1) Na + channelopathies; (2) arrhythmias due to K + channel mutations; and (3) arrhythmias due to other inherited arrhythmogenic mechanisms. Another major goal was to provide recommendations to support, enable, or facilitate research to improve future diagnosis and management of inherited arrhythmias. Classifications of electric heart diseases have proved to be exceedingly complex and in many respects contradictory. A new contemporary and rigorous classification of arrhythmogenic cardiomyopathies is proposed. This consensus report provides an important framework and overview to this increasingly heterogeneous group of primary cardiac membrane channel diseases. Of particular note, the present classification scheme recognizes the rapid evolution of molecular biology and novel therapeutic approaches in cardiology, as well as the introduction of many recently described diseases, and is unique in that it incorporates ion channelopathies as a primary cardiomyopathy in consensus with a recent American Heart Association Scientific Statement.The National Heart, Lung, and Blood Institute and Office of Rare Diseases at the National Institutes of Health organized a workshop (September 14 to 15, 2006, in Bethesda, Md) to advise on new research directions needed for improved identification and treatment of rare inherited arrhythmias. These included the following: (1) Na + channelopathies; (2) arrhythmias due to K + channel mutations; and (3) arrhythmias due to other inherited arrhythmogenic mechanisms. Another major goal was to provide recommendations to support, enable, or facilitate research to improve future diagnosis and management of inherited arrhythmias. Classifications of electric heart diseases have proved to be exceedingly complex and in many respects contradictory. A new contemporary and rigorous classification of arrhythmogenic cardiomyopathies is proposed. This consensus report provides an important framework and overview to this increasingly heterogeneous group of primary cardiac membrane channel diseases. Of particular note, the present classification scheme recognizes the rapid evolution of molecular biology and novel therapeutic approaches in cardiology, as well as the introduction of many recently described diseases, and is unique in that it incorporates ion channelopathies as a primary cardiomyopathy in consensus with a recent American Heart Association Scientific Statement
. 76 Año 26 (2019) mayo-agosto. Dimensión Antropológica
No full text- Introducción. Mover enfoques, otras perspectivas de lectura de los antiguos textos novohispanos por Clementina Battcock. - Los tlatoque en la Decimatercia relación de Fernando de Alva Ixtlilxóchitl por Yukitaka Inoue Okubo. - El relato cosmogónico del Códice Vaticano A. Una reflexión en torno a la tecnología sacrificial y la dinámica cronológica por Ana Díaz Álvarez. - Los textos cristianos en lengua náhuatl del periodo novohispano: fuentes para la historia cultural por Berenice Alcántara Rojas. - Fuentes de las instancias locales del gobierno novohispano: los cabildos y la jurisdicción de Actopan, siglo XVIII por Annia González Torres. - De neófitos a cristianos. Los indios a través de una fuente eclesiástica: 1527-1728 por Berenise Bravo Rubio. - Biografía y archivos: fray Baltasar de Covarrubias, obispo novohispano del siglo XVII por Patricia Escandón. - Los indios del Museo Nacional de Antropología: una mirada paralela por Haydeé López Hernández. - Beatriz Caiuby Labate y Clancy Cavnar (eds.) Peyote. History, Tradition, Politics, and Conservation por Carlo Bonfiglioli. - José Eduardo Zárate Hernández. La celebración de la infancia. El culto al Niño Jesús en el área purhépecha por Claudia Tomic Hernández Rivera
Mechanisms of cAMP compartmentation in cardiac myocytes: experimental and computational approaches to understanding
No full textThe small diffusible second messenger 3’,5’-cyclic adenosine monophosphate (cAMP) is found in virtually every cell in our bodies, where it mediates responses to a variety of different G protein coupled receptors (GPCRs). In the heart, cAMP plays a critical role in regulating many different aspects of cardiac myocyte function, including gene transcription, cell metabolism, and excitation-contraction coupling. Yet, not all GPCRs that stimulate cAMP production elicit the same responses. Subcellular compartmentation of cAMP is essential to explain how different receptors can utilize the same diffusible second messenger to elicit unique functional responses. However the mechanisms contributing to this behavior and its significance in producing physiological and pathological responses are incompletely understood. Mathematical modeling has played an essential role in gaining insight into these questions. This review discusses what we currently know about cAMP compartmentation in cardiac myocytes and questions that are yet to be answered
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