We recently reported that zacopride is a selective inward rectifier potassium current (I
K1) channel agonist, suppressing ventricular arrhythmias without affecting atrial arrhythmias. The present study aimed to investigate the unique pharmacological properties of zacopride. The whole-cell patch-clamp technique was used to study I
K1 currents in rat atrial myocytes and Kir2.x currents in human embryonic kidney (HEK)-293 cells transfected with inward rectifier potassium channel (Kir)2.1, Kir2.2, Kir2.3,
or mutated Kir2.1 (at phosphorylation site S425L). Western immunoblots were performed to estimate the relative protein expression levels of Kir2.x in rat atria and ventricles. Results showed that zacopride did not affect the I
K1 and transmembrane
potential of atrial myocytes. In HEK293 cells, zacopride increased Kir2.1 homomeric channels by 40.7%ñ9.7% at ?50 mV, but
did not affect Kir2.2 and Kir2.3 homomeric channels, and Kir2.1-Kir2.2, Kir2.1-Kir2.3 and Kir2.2-Kir2.3 heteromeric channels. Western immunoblots showed that similar levels of Kir2.3 protein were expressed in rat atria and ventricles, but atrial
Kir2.1 protein level was only 25% of that measured in the ventricle. In addition, 5-hydroxytryptamine (5-HT)3
receptor was
undetectable, whereas 5-HT4
receptor was weakly expressed in HEK293 cells. The Kir2.1-activating effect of zacopride in
these cells was abolished by inhibition of protein kinase A (PKA), but not PKC or PKG. Furthermore, zacopride did not activate the mutant Kir2.1 channel in HEK293 cells but selectively activated the Kir2.1 homomeric channel via a PKA-dependent
pathway, independent to that of the 5-HT receptor.
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Author Name: Li Zhang,ÿQingHua Liu,ÿChengFang Liu,ÿXuWen Zhai
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Keywords: 16747305,Zacopride selectively activates the Kir2.1 channel via a PKA signaling pathway in rat cardiomyocytes,16747305,Li Zhang,ÿQingHua Liu,ÿChengFang Liu,ÿXuWen Zhai,Zacopride selectively activates the Kir2.1 channel via a PKA signaling pathway in rat cardiomyocytes,16747305,Li Zhang,ÿQingHua Liu,ÿChengFang Liu,ÿXuWen Zhai
ISSN: 16747305
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