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

Abstract

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 post synaptic density, discs large, and zonula 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.reentry | scaffolding proteins | conduction velocity | protein trafficking I n the heart, the inward rectifying potassium current (I K1 ) is the major current responsible for the maintenance of the resting membrane potential (RMP), whereas the sodium current (I Na ) provides the largest fraction of the inward depolarizing current that flows during an action potential (1). It is well-known that a relationship exists between these two ionic currents that is crucial for proper cardiac electrical function; disruption of this balance results in changes in sodium channel availability, cell excitability, action potential duration, and conduction velocity (2). Accordingly, I K1 -I Na interactions are important in stabilizing and controlling the frequency of the electrical rotors that are responsible for the most dangerous cardiac arrhythmias, including ventricular tachycardia and fibrillation (3).Post synaptic density, discs large, and zonula occludens-1 (PDZ) domain proteins link different and in many cases, multiple proteins to macromolecular complexes through interactions with their various domains. More than 70 PDZ d...

IK1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes

“…6, A and B). This is consistent with observations from other groups who have found that I Na-P density increases in the presence of Kir2.1 (19). F97C-CAV3 increased I Na-L but did not affect I Na-P in both I K1 -enhanced and iPS-CMs.…”

“…iPS-CM MODEL FOR INVESTIGATING COMPLEX INHERITED ARRHYTHMIAS ability and may increase both peak and late current (1,19). Compared with WT-CAV3, F97C-CAV3-infected iPS-CMs produced an increase in I Na-L without affecting I Na-P .…”

The Interaction of Caveolin 3 Protein with the Potassium Inward Rectifier Channel Kir2.1

“…This is derived from this work and recent work by Abriel and colleagues (27), who demonstrated that Na V 1.5 associates with syntrophin and SAP97, Makielski and colleagues (5,23), who established that Na V 1.5 coimmunoprecipitates with Cav3 and syntrophin, Vandenberg and colleagues, who showed that Kir2.1 coimmunoprecipitates with syntrophin (11), and Anumonwo and colleagues (28), who assert that Kir2.1 associates with SAP97. This is also in agreement with a recent study by Jalife and colleagues (29), who propose reciprocal modulation of Kir2.1 and Na V 1.5 and suggest that these ion channels are in the same macromolecular complex. Although these protein interactions have been shown separately, our findings corroborate these studies, and we demonstrate here pathophysiologic consequences of the association of Cav3 with Kir2.1 and Na V 1.5.…”

The Role of the Ina-Ik1 Complex on Human Ventricular Conduction Velocity

“…The INa-IK1 ion channels form one such complex, recently shown to control cardiac excitability and arrhythmia by Milstein et al [8]. Their inter-species study concluded that an increase in functional expression of one channel reciprocally modulates the expression of the other to maximise cardiac excitability.…”