Abstract
During the repolarization phase of a cardiac action potential, hERG1 K(+) channels rapidly recover from an inactivated state then slowly deactivate to a closed state. The resulting resurgence of outward current terminates the plateau phase and is thus a key regulator of action potential duration of cardiomyocytes. The intracellular N-terminal domain of the hERG1 subunit is required for slow deactivation of the channel as its removal accelerates deactivation 10-fold. Here we investigate the stoichiometry of hERG1 channel deactivation by characterizing the kinetic properties of concatenated tetramers containing a variable number of wild-type and mutant subunits. Three mutations known to accelerate deactivation were investigated, including R56Q and R4A/R5A in the N terminus and F656I in the S6 transmembrane segment. In all cases, a single mutant subunit induced the same rapid deactivation of a concatenated channel as that observed for homotetrameric mutant channels. We conclude that slow deactivation gating of hERG1 channels involves a concerted, fully cooperative interaction between all four wild-type channel subunits.
Highlights
The N terminus of hERG1 subunits modulates the rate of channel deactivation
The activation and deactivation properties of hERG1 channels are not altered by covalent linkage of four WT subunits
Studies of hERG1 channel gating established the importance of the N-terminal eag domain
Summary
The N terminus of hERG1 subunits modulates the rate of channel deactivation. Conclusion: All four subunits cooperate fully to slow the rate of hERG1 channel deactivation. The intracellular N-terminal domain of the hERG1 subunit is caused by de novo or inherited loss of function mutations in required for slow deactivation of the channel as its removal hERG1 slows the rate of action potential repolarization, proaccelerates deactivation 10-fold. 1; eag, ether-a-go-go; LQT2, type 2 long QT syndrome; PAS, Per-Arnt-Sim; deact-f, fast time constant of deactivation; deact-s, slow time constant of deactivation; Vret, return voltage; Vt, test voltage; V0.5, half-point of voltage dependence of activation; ANOVA, analysis of variance; z, equivalent charge; CNBHD, C-linker and a cyclic nucleotide binding homology domain. N-terminal Regulation of hERG1 Deactivation hERG1b cRNA [15] This finding suggests that full-length and N-terminal-truncated subunits cooperate during channel deactivation, but the nature of cooperative interactions (i.e. sequential versus fully concerted) has not been determined. We ask how many wild-type (WT) N termini are required for the homotypic hERG1a channel to deactivate with its characteristic slow kinetics
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
