Related Experiment Video

Updated: Apr 17, 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

PP2 prevents isoproterenol stimulation of cardiac pacemaker activity

Jianying Huang1, Yen-Chang Lin, Stan Hileman

  • 1*Center for Cardiovascular and Respiratory Sciences, West Virginia University, Morgantown, WV; †Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV; ‡Graduate Institute of Biotechnology, Chinese Culture University, Taiwan; §Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV; ¶Department of Neurobiology and Anatomy, West Virginia University, Morgantown, WV; and ‖Heart Institute of Health Sciences Center, West Virginia University, Morgantown, WV. Dr Jianying Huang is now with the Department of Neurology, Yale University School of Medicine, New Haven, CT; Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT; and Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT.

Journal of Cardiovascular Pharmacology
|February 7, 2015
PubMed

Insights

Src tyrosine kinase inhibitor PP2 prevents beta-adrenergic stimulation of cardiac pacemaker activity. This effect involves reduced HCN4 channel function and cell surface expression, impacting heart rate regulation.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Pharmacology

Background:

  • Tyrosine kinase inhibitors (TKIs) used in cancer therapy pose risks for cardiac arrhythmias, such as prolonged QT interval.
  • Src tyrosine kinases play a role in regulating cardiac function.
  • Understanding the mechanisms behind TKI-induced cardiotoxicity is crucial for patient safety.

Purpose of the Study:

  • To investigate the effects of a selective Src tyrosine kinase inhibitor, PP2, on cardiac pacemaker activity.
  • To elucidate the role of HCN4 channels in mediating the effects of PP2 on heart rate.
  • To determine whether PP2's effects are dependent on cAMP signaling.

Main Methods:

  • Experiments were conducted on dissected rat sinus node and isolated sinus node myocytes.
  • The hyperpolarization-activated "funny" current (If) was measured in response to PP2 and isoproterenol.
  • Human embryonic kidney 293 cells overexpressing wild-type and mutant HCN4 channels were used to assess channel function.

Main Results:

  • PP2 inhibited and prevented isoproterenol-stimulated cardiac pacemaker activity in rat sinus node preparations.
  • In sinus node myocytes, PP2 suppressed the If current by negatively shifting its activation curve and decelerating kinetics.
  • PP2 decreased cell surface expression and tyrosine phosphorylation of HCN4 channel proteins, and its effects were partially mediated by a cAMP-independent pathway.

Conclusions:

  • PP2, a Src tyrosine kinase inhibitor, attenuates beta-adrenergic stimulation of cardiac pacemaker activity.
  • This effect is, at least partially, mediated by a cAMP-independent reduction in HCN4 channel activity and cell surface expression.
  • These findings highlight a potential mechanism for TKI-related cardiotoxicity and identify HCN4 channels as key targets.

More Related Videos

Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk05:15

Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk

Published on: July 27, 2022

2.2K
Generation of Murine Cardiac Pacemaker Cell Aggregates Based on ES-Cell-Programming in Combination with Myh6-Promoter-Selection08:52

Generation of Murine Cardiac Pacemaker Cell Aggregates Based on ES-Cell-Programming in Combination with Myh6-Promoter-Selection

Published on: February 17, 2015

10.2K

Related Concept Videos

Antiarrhythmic Drugs: Class II Agents as β-Adrenergic Blockers01:24

Antiarrhythmic Drugs: Class II Agents as β-Adrenergic Blockers

Adrenergic stimulation generally impacts cardiac rate and rhythm. Specifically, stimulation of the β-adrenoceptors triggers an increase in intracellular calcium ion influx and pacemaker currents, which may cause arrhythmias. Catecholamines like adrenaline also demonstrate β2-adrenoceptor-mediated hypokalemia, impacting cardiac action potential and disrupting the normal cardiac rhythm. Class II antiarrhythmic drugs are β-adrenoceptor antagonists or β-blockers, which...
2.4K
Antiarrhythmic Drugs: Class III Agents as Potassium Channel Blockers01:12

Antiarrhythmic Drugs: Class III Agents as Potassium Channel Blockers

Class III antiarrhythmic drugs are a group of medications that can prolong action potentials in the heart. They achieve this by blocking potassium channels or enhancing inward currents from sodium channels. However, these drugs have a unique property of "reverse use-dependence," which is most pronounced at slower heart rates and can lead to torsades de pointes—a specific type of arrhythmia. However, it is essential to note that excessive QT interval prolongation—a measure of...
3.0K
G-Protein Gated Ion Channels01:21

G-Protein Gated Ion Channels

GPCRs are primarily responsible for our sense of smell, taste, and vision.  The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory...
7.4K
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.
2.7K
Cardiac Action Potential01:30

Cardiac Action Potential

Cardiac action potentials are essential for proper heart function, enabling the rhythmic contractions needed for adequate blood circulation. Nodal cells and Purkinje fibers, specialized for electrical conduction, generate these action potentials.
The cardiac action potential process involves a series of phases characterized by the movement of ions across the cardiac cell membranes, leading to the depolarization and repolarization of the cardiac myocytes.
Ionic Basis of Cardiac Action Potentials
11.4K
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...
10.6K