Cardiac Kir2.1 and Na _V 1.5 Channels Traffic Together to the Sarcolemma to Control Excitability

Abstract

The Na1.5-Kir2.1 macromolecular complex pre-assembles early in the forward trafficking pathway. Therefore, disruption of Kir2.1 trafficking in cardiomyocytes affects trafficking of Na1.5, which may have important implications in the mechanisms of arrhythmias in inheritable cardiac diseases.

Brugada syndrome trafficking–defective Nav1.5 channels can trap cardiac Kir2.1/2.2 channels

“…Therefore, the results would indicate that, at least at some stages (biosynthesis and/or forward and retrograde trafficking), Nav1.5 and Kir2.1 proteins do interact, forming complexes. Indeed, previous results from our group demonstrated that at least a pool of Nav1.5 and Kir2.1 channels form complexes early after their synthesis at the ER (8) and that these complexes, whose cellular biology is regulated differently than that of Nav1.5 and Kir2.1 channels alone (7), exhibit preferential forward trafficking toward the membrane (7,8). Interestingly, when a Nav1.5 mutant produces a DNE on Nav1.5, this does not necessarily imply that it concomitantly produces a DNE on Kir2.1/2.2 channels (p.D1690N) and vice versa (p.D1816VfsX7).…”

“…In the 1950s Weidmann (4) established that the encompassed voltage-dependent activity of I Na and I K1 is a major determinant of cardiac excitability and conduction velocity. Furthermore, we demonstrated that the functional expression of Nav1.5 and Kir2.1/Kir2.2 channels is reciprocally regulated (5)(6)(7)(8), a mechanism that probably strengthens control of ventricular excitability.…”

“…The functionality of the pool of Nav1.5 channels not exported through the ER-Golgi membrane route is a matter of debate (28,29), since the fully glycosylated forms of the channel are generated at the Golgi (23). Interestingly, a fraction of Nav1.5 channels associated to Kir2.1 are sensitive to endoglycosidase H (8), which removes only high mannose carbohydrates that are incorporated in the ER (22,30), thus suggesting that a pool of Nav1.5 channels that form part of the Nav1.5-Kir2.1 complexes also bypasses the Golgi. The unconventional secretory route seems to be mediated by GRASP65 and GRASP55 (26,27), which contain 2 PDZ domains at the N-terminus (27) and, besides the Golgi, are located at ER exit sites (31).…”

“…Similarly, the trafficking-defective p.Δ508-CFTR anion channel, which is retained at the ER, can reach the plasma membrane through an unconventional mechanism that is dependent of GRASPs (22). Furthermore, recent data demonstrated that Golgi trafficking-defective Δ314-315 Kir2.1 channels, which are associated to the Andersen-Tawil syndrome because they generate almost no I K1 (32), produced a DNE on I Na (8). Gathering all the results, we propose that Nav1.5 channels that are retained early in the secretory route (mainly the ER and/or the cis-Golgi) can be exported together with Kir2.1 channels via GRASP through the unconventional route.…”

Modelling depolarization delay, sodium currents, and electrical potentials in cardiac transverse tubules

“…A second question concerns the role played by Ttubular sodium current. Although the existence of a T-tubular pool of sodium channels is still under debate (Rougier et al, 2019), several studies have suggested that sodium channels are present in Ttubules and that the T-tubular sodium current may be substantial (Maier et al, 2004;Mohler et al, 2004;Brette and Orchard, 2006;Westenbroek et al, 2013;Koleske et al, 2018;Ponce-Balbuena et al, 2018). To date, the effects of tubular sodium current and the interactions between the sodium current and the extracellular potentials have scarcely been investigated.…”