Long-QT syndrome-associated caveolin-3 mutations differentially regulate the hyperpolarization-activated cyclic nucleotide gated channel 4

Abstract

Background Caveolin-3 (cav-3) mutations are linked to the long-QT syndrome (LQTS) causing distinct clinical symptoms. Hyperpolarization-activated cyclic nucleotide channel 4 (HCN4) underlies the pacemaker current I It associates with cav-3 and both form a macromolecular complex. Methods To examine the effects of human LQTS-associated cav-3 mutations on HCN4-channel function, HEK293-cells were cotransfected with HCN4 and wild-type (WT) cav-3 or a LQTS-associated cav-3 mutant (T78M, A85T, S141R, or F97C). HCN4 currents were recorded using the whole-cell patch-clamp technique. Results WT cav-3 significantly decreased HCN4 current density and shifted midpoint of activation into negative direction. HCN4 current properties were differentially modulated by LQTS-associated cav-3 mutations. When compared with WT cav-3, A85T, F97C, and T78M did not alter the specific effect of cav-3, but S141R significantly increased HCN4 current density. Compared with WT cav-3, no significant modifications of voltage dependence of steady-state activation curves were observed. However, while WT cav-3 alone had no significant effect on HCN4 current activation, all LQTS-associated cav-3 mutations significantly accelerated HCN4 activation kinetics. Conclusions Our results indicate that HCN4 channel function is modulated by cav-3. LQTS-associated mutations of cav-3 differentially influence pacemaker current properties indicating a pathophysiological role in clinical manifestations.

HCN4 Gene Variations in Sudden Unexplained Nocturnal Death Syndrome in the Southern Han Chinese Population,

“…On the other hand, HCN4 channel interacts with many arrhythmia‐related genes/proteins in its pacemaker functioning . Over‐expression or disruption of some arrhythmia‐related proteins was reported to affect HCN4 channel function . Decher et al.…”

“…On the other hand, HCN4 channel interacts with many arrhythmia-related genes/proteins in its pacemaker functioning (28)(29)(30)(31)(32). Over-expression or disruption of some arrhythmiarelated proteins was reported to affect HCN4 channel function (28)(29)(30). Decher et al (28) discovered that co-expressed KCNE2 enhanced HCN4 generated currents in both Xenopus oocytes and Chinese Hamster ovary (CHO) cells might be accomplished by interaction between carboxy-terminal tail of KCNE2 and that of HCN4.…”

Caveolin-3 and Arrhythmias: Insights into the Molecular Mechanisms

“…Hyperpolarization-activated cyclic nucleotide channel 4(HCN4), also named the pacemaker channel, is the dominant isoform of the sinus node region interacting with caveolin-3 [ 67 ]. HCN4 channel function is negatively modulated by caveolin-3 to modulate the channel’s activity [ 68 ]. Of note, increased I HCN4 activity in the ventricle was shown to provoke ventricular automaticity resulting in ventricular arrhythmias [ 69 ].…”

Sudden Cardiac Death in Young Athletes: Literature Review of Molecular Basis

“…99 Mutations in genes encoding other ionchannel associated proteins, such as caveolin (CAV3), ankyrins (ANK3, ANK2), syntrophin (SNTA1), and yotiao (AKAP-9) are now implicated in the genesis of the cardiac channelopathies, although they affect only a very small proportion of arrhythmic patients. 94,[100][101][102][103][104][105][106][107]…”