Related Experiment Video

Updated: Mar 26, 2026

Dual-Dye Optical Mapping of Hearts from RyR2R2474S Knock-In Mice of Catecholaminergic Polymorphic Ventricular Tachycardia
09:36

Dual-Dye Optical Mapping of Hearts from RyR2R2474S Knock-In Mice of Catecholaminergic Polymorphic Ventricular Tachycardia

Published on: December 22, 2023

1.9K

Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca(2+)-dependent inactivation

Ivy E Dick1, Rosy Joshi-Mukherjee1, Wanjun Yang1

  • 1Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.

Nature Communications
|January 30, 2016
PubMed

Insights

Timothy Syndrome (TS) involves cardiac arrhythmias due to CaV1.2 channel mutations. This study reveals distinct mechanisms for G406R and G402S variants impacting calcium-dependent inactivation, offering therapeutic insights.

Area of Science:

  • Molecular biology
  • Cardiovascular physiology
  • Genetics

Background:

  • Timothy Syndrome (TS) is a rare genetic disorder affecting multiple systems, primarily the heart.
  • TS is characterized by prolonged cardiac action potentials and life-threatening arrhythmias.
  • The condition arises from specific de novo missense mutations (G406R or G402S) in the CaV1.2 calcium channel gene.

Purpose of the Study:

  • To investigate the effects of Timothy Syndrome-associated CaV1.2 channel mutations (G406R and G402S) on calcium-dependent inactivation (CDI).
  • To elucidate the distinct molecular mechanisms underlying the G406R and G402S variants' impact on channel function.
  • To explore the relationship between TS channel expression levels and arrhythmia induction in cardiac myocytes.

Main Methods:

  • Utilized electrophysiological techniques to assess CaV1.2 channel function, specifically focusing on CDI.
  • Employed cultured adult guinea pig myocytes to study the physiological impact of TS channel expression.
  • Integrated experimental data with a quantitative ventricular myocyte model to simulate arrhythmia development.

Main Results:

  • Identified a significant defect in calcium-dependent inactivation (CDI) in Timothy Syndrome (TS) CaV1.2 channels.
  • Uncovered a notable divergence in the underlying mechanisms between the G406R and G402S TS channel variants.
  • Demonstrated a threshold effect in arrhythmia induction related to the proportion of mutant versus wild-type TS channels.

Conclusions:

  • The G406R and G402S mutations in CaV1.2 channels, while causing similar voltage-dependent inactivation defects, exhibit distinct effects on CDI.
  • A quantitative understanding of TS channel behavior in myocytes suggests that modulating the mutant/wild-type channel ratio could be a therapeutic strategy.
  • These findings provide crucial insights into the pathophysiology of Timothy Syndrome and potential avenues for clinical intervention.

More Related Videos

Microelectrode Array Recording of Sinoatrial Node Firing Rate to Identify Intrinsic Cardiac Pacemaking Defects in Mice09:20

Microelectrode Array Recording of Sinoatrial Node Firing Rate to Identify Intrinsic Cardiac Pacemaking Defects in Mice

Published on: July 5, 2021

3.7K
Isolation of Human Atrial Myocytes for Simultaneous Measurements of Ca2+ Transients and Membrane Currents10:53

Isolation of Human Atrial Myocytes for Simultaneous Measurements of Ca2+ Transients and Membrane Currents

Published on: July 3, 2013

21.2K

Related Concept Videos

Mechanism of Cardiac Arrhythmias01:28

Mechanism of Cardiac Arrhythmias

Arrhythmias are irregular heart rhythms occurring when the heart's electrical impulses become abnormal. These disturbances can lead to various symptoms, depending on their severity and the underlying cause. Some common factors contributing to arrhythmias include hypoxia, ischemia, electrolyte imbalances, excessive catecholamine exposure, drug toxicity, and muscle overstretching. Arrhythmias can be classified into two main types based on the rate and site of origin of abnormal heart rhythms.
2.6K
Disturbances in Heart Rhythm01:29

Disturbances in Heart Rhythm

Arrhythmia or dysrhythmia refers to an abnormal heart rhythm caused by a defect in the heart's conduction system. It can cause the heart to beat irregularly, too quickly, or too slowly, leading to symptoms like chest pain, shortness of breath, and fainting. Factors such as stress, caffeine, alcohol, nicotine, cocaine, certain drugs, congenital defects, diseases, and electrolyte abnormalities can trigger arrhythmias.
Arrhythmias are categorized by their speed, rhythm, and origin. A slow heart...
3.5K
Electrophysiology of Normal Cardiac Rhythm01:19

Electrophysiology of Normal Cardiac Rhythm

The normal cardiac rhythm is a synchronized electrical activity that facilitates the regular and coordinated contraction of the heart muscle. This process is essential for efficient blood circulation throughout the body. The fundamental elements involved in establishing and maintaining this rhythm include the unique electrical properties of cardiac muscle cells, the sinoatrial (SA) node's pacemaker function, the specialized conducting system, and the ionic mechanisms underlying each phase...
10.3K
Antiarrhythmic Drugs: Class IV Agents as Calcium Channel Blockers01:20

Antiarrhythmic Drugs: Class IV Agents as Calcium Channel Blockers

Class IV antiarrhythmic drugs, such as verapamil and diltiazem, block calcium channels. They primarily affect the heart, slowing the conduction in calcium-dependent tissues like the SA and AV nodes. These drugs manage reentrant supraventricular tachycardia (SVT) and reduce ventricular rate in atrial flutter/fibrillation.
Verapamil, a calcium channel blocker, inhibits calcium movement across myocardial cell membranes and vascular smooth muscle. This results in the dilation of coronary and...
2.6K
Dysrhythmias I: Introduction01:15

Dysrhythmias I: Introduction

Dysrhythmias refers to abnormalities in the heart's rhythm. They result from disruptions in the heart's electrical conduction system, which includes the sinoatrial(SA)node, atrioventricular(AV) node, the bundle of His, bundle branches, and Purkinje fibers.Definition and PathophysiologyDysrhythmias result from disorders of impulse formation, impulse conduction, or both. The heart contains specialized cells in the sinoatrial node, atrioventricular node, and the bundle of His and Purkinje fibers...
779
Dysrhythmias IV: Characteristics of Bradyarrhythmias01:18

Dysrhythmias IV: Characteristics of Bradyarrhythmias

Bradyarrhythmias are cardiac rhythm disorders characterized by a slower-than-normal heart rate, typically defined as fewer than 60 beats per minute. Some of which are discussed here:Sinus BradycardiaSinus bradycardia presents a heart rate lower than 60 beats per minute, with a regular rhythm originating from the SA node. The ECG typically shows normal P waves preceding each QRS complex, a normal PR interval (0.12 to 0.20 seconds), and a normal QRS duration (0.06 to 0.10 seconds).First-Degree AV...
801