Differential modulation of late sodium current by protein kinase A in R1623Q mutant of LQT3.
OBJECTIVE
In the type 3 long QT syndrome (LQT3), shortening of the QT interval by overdrive pacing is used to prevent life-threatening arrhythmias. However, it is unclear whether accelerated heart rate induced by beta-adrenergic agents produces similar effects on the late sodium current (I(Na)) to those by overdrive pacing therapy. We analyzed the beta-adrenergic-like effects of protein kinase A and fluoride on I(Na) in R1623Q mutant channels.


METHODS
cDNA encoding either wild-type (WT) or R1623Q mutant of hNa(v)1.5 was stably transfected into HEK293 cells. I(Na) was recorded using a whole-cell patch-clamp technique at 23 degrees C.


RESULTS
In R1623Q channels, 2 mM pCPT-AMP and 120 mM fluoride significantly delayed macroscopic current decay and increased relative amplitude of the late I(Na) in a time-dependent manner. Modulations of peak I(Na) gating kinetics (activation, inactivation, recovery from inactivation) by fluoride were similar in WT and R1623Q channels. The effects of fluoride were almost completely abolished by concomitant dialysis with a protein kinase inhibitor. We also compared the effect of pacing with that of beta-adrenergic stimulation by analyzing the frequency-dependence of the late I(Na). Fluoride augmented frequency-dependent reduction of the late I(Na), which was due to preferential delay of recovery of late I(Na). However, the increase in late I(Na) by fluoride at steady-state was more potent than the frequency-dependent reduction of late I(Na).


CONCLUSIONS
Different basic mechanisms participate in the QT interval shortening by pacing and beta-adrenergic stimulation in the LQT3.
Tsurugi
Takuo
T
Second Department of Internal Medicine, University of Occupational and Environmental Health Japan, Kitakyushu 807-8555, Japan.
Nagatomo
Toshihisa
T
Abe
Haruhiko
H
Oginosawa
Yasushi
Y
Takemasa
Hiroko
H
Kohno
Ritsuko
R
Makita
Naomasa
N
Makielski
Jonathan C
JC
Otsuji
Yutaka
Y
D000200:Action Potentials / Q000187:drug effects; D002460:Cell Line; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005459:Fluorides / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008133:Long QT Syndrome / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics*; D013873:Thionucleotides / Q000494:pharmacology; D014162:Transfection
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D047428:Protein Kinase Inhibitors; C568320:SCN5A protein, human; D015222:Sodium Channels; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005459:Fluorides