Modulation of human ether a gogo related channels by CASQ2 contributes to etiology of catecholaminergic polymorphic ventricular tachycardia (CPVT).
BACKGROUND
The plateau phase of the ventricular action potential is the result of balanced Ca(2+) influx and K(+) efflux. The action potential is terminated by repolarizing K(+) currents. Under β-adrenergic stimulation, both the Ca(2+)-influx and the delayed rectifier K(+) currents I(K) are stimulated to adjust the cardiac action potential duration to the enhanced heart rate and to ascertain adequate increase in net Ca(2+) influx. Intracellularly, a Calsequestrin2 (CASQ2)-ryanodine receptor complex serves as the most effective Ca(2+) reservoir/release system to aid the control of intracellular Ca(2+) levels. Currently, it is unclear if disease-associated CASQ2 gene variants alter intracellular free Ca(2+) concentrations and if cardiac ion channels are affected by it.


OBJECTIVE
The goal of this study is to test if CASQ2 determines intracellular free Ca(2+) concentrations and to identify cardiac ion channels that are affected by it. Further, we aim to study disease-associated CASQ2 gene variants in this context.


RESULTS
Here, we study the effects of the CASQ2 mutations R33Q, F189L, and D307H, located in highly conserved regions, on the functions of cardiac potassium channels in Xenopus oocytes using two electrode voltage clamp. As a result, CASQ2 wild type and CASQ2-mutants modulated hERG functions differently. Free Ca(2+) measurements and molecular dynamics simulations imply alterations in Ca(2+) buffer capacity paralled by changes in the dynamic behavior of the CASQ2-mutants compared to CASQ2 wild type.


CONCLUSIONS
These in vitro and in silico data suggest a regulatory role of CASQ2 on cytosolic Ca(2+) and hERG channels which may contribute to the etiology of CPVT.
Department of Biochemistry I, Ruhr-University Bochum, Bochum, Germany.
Karina
K
Eckey
Nathalie
N
Strutz-Seebohm
Guy
G
Katz
Gloria
G
Fuhrmann
Ulrike
U
Henrion
Lutz
L
Pott
Wolfgang A
WA
Linke
Michael
M
Arad
Florian
F
Lang
Guiscard
G
Seebohm
D000200:Action Potentials / Q000502:physiology; D019943:Amino Acid Substitution; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002155:Calsequestrin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000209:etiology; D014981:Xenopus / Q000254:growth & development; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
C443109:CASQ2 protein, human; D002155:Calsequestrin; D051638:Ether-A-Go-Go Potassium Channels; D019837:Ryanodine Receptor Calcium Release Channel; D011188:Potassium; D002118:Calcium