Session S83.5

Allosteric Interaction of Rapid Delayed Rectifier Protein and Its Role in Cardiac Repolarization

C Wang*, P Beyerlein, P Hammer, A Krause,
CD Nugent, W Dubitzky

University of Ulster
Coleraine, Northern Ireland, UK

The malfunction of the rapid delayed rectifier (Ikr) due to the structure modification by mutations has been linked to inheritable long QT syndrome. The a-subunit of Ikr has been identified to be composed of multiple function domains. However, much less is known about its interaction properties in the assembled channel protein and its electrophysiological role.
In this paper, we present a detailed conformational kinetic model at physiological temperature through characterizing allosteric interactions between the voltage sensing domain and the cytoplasmic activation gate. The correlation of kinetic properties to action potential (AP) dynamics was investigated through incorporating the conformational model into a guinea pig cell model at different basic cycle lengths (BCLs).
Based on our experiments we found that in response to driving forces ranging from -40 mV to 60 mV, two open states were populated. An early uprise of Ikr during the phase 1 of the AP exhibited more than a 6-fold increment at a BCL of 400 ms compared with a BCL of 1000 ms. This elevation at the early AP was attributable to an available reserve developed from larger occupancy in transient heteromeric pore conformations, leading to shortening of the action potential duration at rapid rates. In contrast, the development of a dominant late peak Ikr with a steep slope morphology observed at slow rates arose from the allosteric coupled activation pathway, allowing for its participating in the repolarizing process during phases 2 and 3 of the AP.
In conclusion to our study we have found that the existence of available reserve suggests Ikr has a repolarization reserve which facilities its rate adaptation under physiological conditions. The allosteric coupling of activating and opening explains why Ikr is a major repolarizing force during the plateau and late phases of the AP, implying that any reduction of Ikr due to genetic mutations causes delayed ventricular repolarization under bradycardia conditions, predisposing the affected individuals to long QT syndrome.

(Abstract Control Number: 113)