Microscopic mechanisms for long QT syndrome type 1 revealed by single-channel analysis of IKs with S3 domain mutations in KCNQ1

Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.1

“…To test whether the N-AT-induced increase in G max is due to changes in the single-channel conductance or the open probability Po, we measure the effect of N-AT on G max of the K v 7.1 mutants S209F and I204F, which have reported open probabilities Po of 0.4 and 0.04, respectively, compared to 0.2 for WT K v 7.1+KCNE1 (Eldstrom et al,2015). If N-AT increases G max by increasing the single-channel conductance, we expect the same increase for these two mutants compared to WT K v 7.1+KCNE1, because they all have the same reported single-channel conductance (Eldstrom et al, 2015).…”

“…To test whether the N-AT-induced increase in G max is due to changes in the single-channel conductance or the open probability Po, we measure the effect of N-AT on G max of the K v 7.1 mutants S209F and I204F, which have reported open probabilities Po of 0.4 and 0.04, respectively, compared to 0.2 for WT K v 7.1+KCNE1 (Eldstrom et al,2015). If N-AT increases G max by increasing the single-channel conductance, we expect the same increase for these two mutants compared to WT K v 7.1+KCNE1, because they all have the same reported single-channel conductance (Eldstrom et al, 2015). However, if N-AT increases G max by stabilizing the open conducting filter and thereby increases Po, we expect smaller G max effects on the “high Po” K v 7.1/S209F+KCNE1 mutant than on WT K v 7.1+KCNE1, because the mutant already has an increased Po in control solution and there is therefore no room for much more increase in Po by PUFAs.…”

“…The effect of N-AT was modeled as a shift of the voltage dependence of Δ V 50 = −30 mV for the first step and an increase in the equilibrium constant by a factor of L PUFA = 1.9 for the second step. Due to the modal behavior of single K V 7.1+KCNE1 channels, we had to calculate the predicted N-AT effect on each of the published single-channel traces for WT and the S209F mutation (Eldstrom et al, 2015) and then adjust the Popen in the macroscopic three-state model to Popen = 0.4 for WT and Popen = 0.66 for S209F mutant (and we call these effective Popen), to get the effective Popen in the macroscopic three-state model to display the expected G max increase as calculated from the single-channel data (see Experimental Procedures for details).…”

KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1

“…Through community initiation, those diagnosed with LQTS and their relatives (∼800) have participated in our research which identified a novel c.613 G>A missense variant in KCNQ1 . As previously described, this mutation results in a valine to methionine substitution at position 205 (p.V205M) in Kv7.1's S3 transmembrane region and negatively impacts I Ks by slowing activation and accelerating deactivation 11 12. Besides the functional evidence for loss-of-function, a prolonged QTc segregates with p.V205M-positive status compared with variant-negative relatives and associated sudden cardiac death (SCD) further supports its designation as a LQTS1 pathogenic variant 10 11.…”

Understanding the microscopic mechanisms for LQT1 needs a global view of the IKs channel

“…In this issue of Heart Rhythm , David Fedida’s group reports the ‘microscopic mechanisms’ for LQT1 revealed by single channel analysis of I Ks 3 . They studied four LQT1-related mutations (D202H, I204F, V205M, and S209F) that occur in the S3 segment of the KCNQ1 channel.…”