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Articles in PresS, published online ahead of print October 3, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00220.2002
Submitted on March 13, 2002
Accepted on September 17, 2002
1 Department of Molecular Pharmacology, Merck Research Laboratories, West Point, PA, USA
* To whom correspondence should be addressed. E-mail: joseph_salata{at}merck.com.
We established HEK-293 cell lines that stably express functional canine ether-a -go-related gene (cERG) potassium channels and examined their biophysical and pharmacological properties with whole-cell patch clamp and [35S]-MK-499 binding displacement. Functionally, cERG current had all the hallmarks of cardiac IKr. Channel opening was time- and voltage-dependent with a threshold near -40mV. The V1/2 for activation was -7.8±2.4mV at 23°C, shifting to -31.9±1.2mV at 36°C. Channels activated with a time constant of 13±1ms at +20mV, showed prominent inward rectification at depolarized potentials, were highly K+ selective (PNa/PK=0.007), and were potently inhibited by IKr blockers. Astemizole, terfenadine, cisapride and MK-499 inhibited cERG and hERG currents with IC50's of 1.3, 13, 19, 15nM, and 1.2, 9, 14, 21nM; and competitively displaced [35S]-MK-499 binding from cERG and hERG with IC50's of 0.4, 12, 35, 0.6nM, and 0.8, 5, 47, 0.6nM, respectively. cERG channels had biophysical properties appropriate for canine action potential repolarization and were pharmacologically sensitive to agents known to prolong QT. A novel MK-499 binding assay provides a new tool to detect agents affecting ERG channels.
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