A rapidly activating delayed rectifier K+ current regulates pacemaker activity in adult mouse sinoatrial node cells

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Electrophysiology

Background:

• The sinoatrial node (SAN) is the heart's natural pacemaker, regulating heart rate through electrical activity.
• The rapidly activating delayed rectifier potassium current (IKr) is a key determinant of cardiac action potential repolarization.

Purpose of the Study:

• To investigate the physiological role of IKr in pacemaker activity within isolated mouse SAN myocytes.
• To examine the expression of mouse ether-a-go-go (mERG) genes in the adult mouse SAN.

Main Methods:

• Voltage clamp electrophysiology was used on isolated SAN cells to characterize E-4031-sensitive currents (IKr).
• The impact of IKr on action potential repolarization and diastolic depolarization was simulated.
• The effect of E-4031 on spontaneous heart rate was assessed in Langendorff-perfused mouse hearts.
• mRNA expression of mERG1 isoforms (mERG1a, mERG1a", mERG1b) in the SAN was analyzed.

Main Results:

• E-4031 significantly inhibited outward currents and blocked tail currents in SAN cells, confirming the presence and characteristics of IKr.
• IKr peaked near -25 mV and deactivated during diastole, contributing to action potential repolarization.
• Pharmacological blockade of IKr with E-4031 reduced heart rate by an average of 36.5%.
• Multiple mERG1 isoforms (mERG1a, mERG1a", mERG1b) were detected in the adult mouse SAN.

Conclusions:

• IKr plays a significant physiological role in regulating pacemaker activity in the adult mouse SAN.
• Multiple mERG1 isoforms likely contribute to the native SAN IKr.
• This study provides the first detailed characterization of IKr in adult mouse SAN cells.