Allosteric interaction of rapid delayed rectifier protein and its role in cardiac repolarization

The alpha-subunit of the rapid delayed rectifier I_kr has been identified to be composed of multiple function domains. However, much less is known about the electrophysiological consequences of the interaction properties in the assembled channel protein. In this paper, we present a detailed conformational kinetic model 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 at different basic cycle lengths. We found that in response to driving forces ranging from -40 mV to 60 mV, two open states were populated. A significant elevation of I_kr at the early AP was attributable to an available reserve and the open-state accumulation, leading to shortening of AP 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. The existence of available reserve suggests I_kr has a repolarization reserve which facilitates its rate adaptation.