Impaired adrenergic/protein kinase A response of slow delayed rectifier potassium channels as a long QT syndrome motif: importance and unknowns

Publication date: Available online 24 November 2018Source: Canadian Journal of CardiologyAuthor(s): Marcela Policarová, Tomáš Novotný, Markéta BébarováAbstractThe slow delayed rectifier potassium current (IKs) significantly contributes to cardiac repolarization under specific conditions, particularly at stimulation by the protein kinase A (PKA) during increased sympathetic tone. Impaired PKA-mediated stimulation of IKs channels may considerably aggravate dysfunction of the channels induced by mutations in the KCNQ1 gene that encodes structure of the α-subunit of IKs channels. These mutations are associated with several subtypes of inherited arrhythmias, mainly long QT syndrome type 1, less commonly short QT syndrome type 2 and atrial fibrillation. The impaired PKA-reactivity of IKs channels may significantly increase the risk of arrhythmia in these patients. Unfortunately, only about 2.7% of the KCNQ1 variants identified as putatively clinically-significant have been studied with respect to this problem. This review summarizes current knowledge in the field in order to stress the importance of PKA-mediated regulation of IKs channels, and to appeal for further analysis of this regulation in KCNQ1 mutations associated with inherited arrhythmogenic syndromes. Based on the facts summarized in our review, we suggest several new regions of the α-subunit of the IKs channels as potential contributors to PKA stimulation, namely the S4 and S5 segments, and the S2-S3 and S4-S5 ...
Source: Canadian Journal of Cardiology - Category: Cardiology Source Type: research