Dynamic Pip2-Iks Interactions Mediate Cardiac Rate Adaptation

Abstract

Rate adaptation is the physiological shortening of the cardiac action potential duration as heart rate increases. Rate adaptation protects the diastolic interval and maintains electrical stability of the cardiac myocyte. Inherited mutations that decrease the cardiac IKs current predispose patients to arrythmias that manifest during stress or exercise, suggesting that IKs plays a prominent role in limiting action potential duration under conditions where heart rate is fast and beta-adrenergic tone is elevated. Using computational models of IKs, Silva et al. were able to reproduce rate adaptive behavior. In their model, IKs channel can occupy readily recruitable- (shallow) or functionally silent- (deep) closed states at rest. However, the molecular basis of the deep-closed states was unknown, and it was empirically modeled as an additional, slow voltage-sensor transition. In a recent study of Kv7.1, the principal subunit of the IKs channel, we found that binding of the lipid phosphatidylinositol 4,5-bisphosphate (PIP2) is required to couple voltage-sensor activation to pore-opening. Here we study the properties of PIP2 interaction with hIKs channels and describe three phenomena: a large reserve of PIP2 unbound channels that exists in biological membranes, the kinetics of PIP2 binding and unbinding are slow, and the activated-open state has a much greater apparent affinity for PIP2 compared to other gating states. Based on these experimentally observed properties we propose that PIP2 binding is the molecular basis for the mode switching behavior in the model by Silva et al., and it underlies spontaneous adaptation of IKs current to changes in cycle length. We test these hypotheses using kinetic and cellular computational models and experimental protocols simulating fast heart rates.