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Natural Agonists of Ryanodine Receptors: Structure-function Relationship and Antiarrhythmic Properties

兰尼定受体的天然激动剂：结构-功能关系和抗心律失常特性

基本信息

批准号：
9905552
负责人：
Hector H Valdivia
金额：
$ 46.32万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905552
关键词：
Active Sites Acute Adrenergic alpha-Antagonists Affinity Agonist Amino Acids Animal Model Animals Arrhythmia Binding Binding Sites Calcium Calcium Channel Cardiac Myocytes Cardiomyopathies Catecholaminergic Polymorphic Ventricular Tachycardia Cell physiology Cells Cellular Membrane Central Core Myopathy Characteristics Charge Communities Complex Disadvantaged Dissociation Dose Enzyme Activation Functional disorder Generations Goals Heart Heart failure Hyperactive behavior Ions Kinetics Ligands Location Malignant hyperpyrexia due to anesthesia Maps Metabolic Molecular Muscle Cells Myocardium Names Penetration Peptides Pharmacology Plant alkaloid Play Property Proteins Receptor Activation Recombinants Regulation Research Role RyR2 Ryanodine Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Sarcoplasmic Reticulum Scorpion Venoms Scorpions Signal Transduction Skeletal Muscle Specificity Speed Structure Structure-Activity Relationship Syndrome Testing Transcriptional Regulation Venoms Ventricular dipole moment experimental study functional group imperatoxin A multidisciplinary mutant novel prevent programs receptor receptor function receptor structure function success thermostability

项目摘要

ABSTRACT Ryanodine receptors (RyR) are sarcoplasmic reticulum Ca2+ release channels that play a critical role in Ca2+ signaling of excitable and non-excitable cells. RyRs owe their name to the fact that they were characterized in great part thanks to ryanodine, a plant alkaloid that binds to RyRs with high affinity and specificity. Ryanodine has been an invaluable ligand of RyRs, but its functional effects are complex and hamper its use in cellular studies. In search of novel ligands that could overcome some of the functional and structural disadvantages of ryanodine, we found in the venom of selected scorpions a set of peptide ligands, termed calcins, displaying high affinity and exquisite selectivity against RyRs. The defining characteristic of calcins is their capacity to stabilize RyR openings in a long-lasting subconducting state. This effect is nearly analogous to that of ryanodine, but unlike ryanodine, calcins bind rapidly to RyRs (fast association rate), freely dissociate from their binding site (reversible effect), display a dose- and sequence-variable effect, and are amenable for derivatization without undergoing major loss in receptor affinity. Calcins also modulate intracellular Ca2+ in intact cardiomyocytes with remarkable speed and with several degrees of potency, thus entering the field as the first cell-penetrating peptides (CPP) RyR-specific Ca2+ mobilizer of high dynamic range. This research program will characterize first and then exploit this novel group of peptide ligands to unravel fundamental mechanisms of RyR function at the molecular, cellular and whole heart level. Our multidisciplinary program, with well-defined deliverables and milestones, may be enveloped in two specific aims. In the first aim, we will first identify and modify the structural domains of calcins involved in RyR recognition and cell penetration to generate a group of functionally diverse CPPs capable of modulating RyR function with wide dynamic range and of delivering cargo to the interior of cardiomyocytes. In the second aim, we will use native and mutant calcins on intact cardiomyocytes, Langendorff-perfused working hearts and intact animals to create acute or sustained periods of RyR hyperactivity and reveal mechanisms of RyR gating, SR Ca2+ load and Ca2+-triggered arrhythmias. These studies use animal models of catecholaminergic polymorphic ventricular tachycardia to develop a novel paradigm for the treatment of calcium-dependent arrhythmias; results may be applied to other cardiomyopathies where controlled unloading of SR Ca2+ may be desirable.

摘要