Journal Article

Dynamic reciprocity of sodium and potassium channel expression in a macromolecular complex controls cardiac excitability and arrhythmia

Martens, Jeffrey R., Auerbach, David S., Furspan, Philip B., Schumacher, Sarah M., Musa, Hassan, Balbuena, Daniela Ponce, Hu, Bin, Jalife, José, Milstein, Michelle L., Anumonwo, Justus M. B., Vaidyanathan, Ravi, Hou, Luqia

2012

Overview

The cardiac electrical impulse depends on an orchestrated interplay of transmembrane ionic currents in myocardial cells. Two critical ionic current mechanisms are the inwardly rectifying potassium current (I K1 ), which is important for maintenance of the cell resting membrane potential, and the sodium current (I Na ), which provides a rapid depolarizing current during the upstroke of the action potential. By controlling the resting membrane potential, I K1 modifies sodium channel availability and therefore, cell excitability, action potential duration, and velocity of impulse propagation. Additionally, I K1 –I Na interactions are key determinants of electrical rotor frequency responsible for abnormal, often lethal, cardiac reentrant activity. Here, we have used a multidisciplinary approach based on molecular and biochemical techniques, acute gene transfer or silencing, and electrophysiology to show that I K1 –I Na interactions involve a reciprocal modulation of expression of their respective channel proteins (Kir2.1 and Na V 1.5) within a macromolecular complex. Thus, an increase in functional expression of one channel reciprocally modulates the other to enhance cardiac excitability. The modulation is model-independent; it is demonstrable in myocytes isolated from mouse and rat hearts and with transgenic and adenoviral-mediated overexpression/silencing. We also show that the p ost synaptic density, d iscs large, and z onula occludens-1 (PDZ) domain protein SAP97 is a component of this macromolecular complex. We show that the interplay between Na v 1.5 and Kir2.1 has electrophysiological consequences on the myocardium and that SAP97 may affect the integrity of this complex or the nature of Na v 1.5–Kir2.1 interactions. The reciprocal modulation between Na v 1.5 and Kir2.1 and the respective ionic currents should be important in the ability of the heart to undergo self-sustaining cardiac rhythm disturbances.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Action Potentials / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Animals / Arrhythmias, Cardiac - genetics / Arrhythmias, Cardiac - mortality / Arrhythmias, Cardiac - physiopathology / Biological Sciences / Cardiac arrhythmia / Cells / Discs Large Homolog 1 Protein / Gene Expression Regulation / Gene Silencing / Guanylate Kinases - genetics / Guanylate Kinases - metabolism / Heart / Membrane Potentials / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mice / Mice, Transgenic / Muscle Proteins - biosynthesis / Muscle Proteins - genetics / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / NAV1.5 Voltage-Gated Sodium Channel / Phosphoproteins - genetics / Phosphoproteins - metabolism / PNAS Plus / PNAS PLUS (AUTHOR SUMMARIES) / Potassium Channels, Inwardly Rectifying - biosynthesis / Potassium Channels, Inwardly Rectifying - genetics / Proteins / Rats / Rats, Sprague-Dawley / Rats, Transgenic / Rodents / Sodium / Sodium Channels - biosynthesis / Sodium Channels - genetics / Zonula Occludens-1 Protein