Effects of IQM-110 on Kv1.5/Kvß2.1 channels

The outward potassium current IKur is the main responsible of the atrial repolarization process and it is generated by the activation of KV1.5 channels, widely expressed in human atria. It is known that mutations in KCNA5 gene, which induce both gain- and loss-of-function in KV1.5 channel, enhance atrial fibrillation susceptibility. Thus, these channels represent a pharmacological target for the development of antiarrhythmic drugs useful in the treatment of supraventricular arrhythmias. KV1.5 channels assembly with several regulatory subunits such as KVß. It has been described that KVß2.1 interacts with KV1.5. Our research group has demonstrated that the molecule IQM-110 produces electrophysiological effects on the KV1.5. The aim of the present study is to analyze the electrophysiological effects of IQM-110 on KV1.5 channels when it was expressed together with the regulatory subunit KVß2.1. In order to achieve this objective, Ltk- cell line constitutively expressing KVß2.1 and with an induced expression of KV1.5 were used. Currents were recorded using the whole-cell configuration of the patch-clamp technique. The effects of IQM-110 on KV1.5/Kvß2.1 current were concentration-dependent with an IC50 of 166¿M (n=64). This compound at 100¿M produced a time-dependent block, inducing a: 1) faster activation (¿=2.8±0.3 vs. 4.1±0.3 ms, n=10, p<0.01), 2) faster inactivation reducing the slow time constant, (¿slow=3172.6±113.8 vs. 629.1±43.8ms, n=5, p<0.001), and 3) slower deactivation kinetics, (¿slow=73.5±3.5 vs. 115.2±12.1ms and ¿fast=19.5±1.3 vs. 27.9±1.9ms, n=10, p<0.01 and p<0.5 respectively). These results are consistent with an open channel block mechanism. Finally, IQM-110 (100 ¿M) enhanced the degree of use-dependent block of the current (1.7±0.4 vs. 47.7±2.4%, n=5, p<0.001). This phenomenon was explained by a slowing of the recovery process in the presence of IQM-110 (¿r=462.6±94.9 vs. 3545.0±254.1ms, n=5, p<0.001). In summary, IQM-110 modulates KV1.5/KVß2.1 channel