Got Rhythm?

Sodium channels are key in the establishment of action potentials (the drivers of our heartbeat), and dysfunction of voltage-gated sodium channel 1.5 (Na_v1.5) in the heart can trigger life-threatening arrhythmias. Despite their significance, however, little is known about the structure and physiological function of these channels.

William Catterall and colleagues used cryo-electron microscopy to construct a complete model of Na_v1.5’s structure at a resolution of 3.5 Å (1). The result? A more comprehensive understanding of what makes the channels unique – namely, an unexpected glycosyl moiety and the loss of disulfide bonding capability at specific subsites – and advanced insight into mechanisms of voltage-dependent channel functions and sodium ion conduction. The team was keen to understand how antiarrhythmic drugs were interacting with Na_v1.5 at an atomic level. “We’ve been able to characterize how flecainide – a commonly prescribed antiarrhythmic – specifically targets the central pore cavity of Na_v1.5, physically blocking sodium permeation,” says Catterall.

Looking ahead, the team plan to image multiple arrhythmic mutations and antiarrhythmic drugs at the atomic level. “This will provide much-needed chemical information, which will facilitate structure-based drug design.”