Barium block of Kir2 and human cardiac inward rectifier currents: evidence for subunit-heteromeric contribution to native currents

Background: Kir2 subunits are believed to underlie the cardiac inwardly rectifying current I-K1. The subunit composition of native I-K1 currents is uncertain, and it has been suggested that heteromultimer formation may play a role. Methods: We studied Ba2+ block of homo- and heteromeric Kir2 channels in Xenopus oocytes and compared the properties observed to those of human cardiac I-K1 in cells isolated from myocardial biopsies of normal human hearts. Results: Homomeric expression of Kir2.1 and Kir2.3 produced currents with similar Ba2+ sensitivities (e.g. IC50 at -120 mV: 16.2+/-3.4, n=11 and 18.5+/-2.1, n=10, respectively), but these were less sensitive to Ba2+ than native I-K1 (4.7+/-0.5 muM, n=10, P=0.001, P<0.001, respectively) and had different Ba2+ blocking kinetics from cardiac I-K1, Kir2.2 sensitivity was similar to cardiac I-K1 (e.g., 2.8+/-0.4 μM, Kir2.2, n=9, vs. 4.7+/-0.5 μM for I-K1), but the blocking kinetics of Kir2.2 were faster than those of I-K1. Currents resulting from co-expression of Kir2 subunits had similar Ba2+ sensitivities and blocking kinetics among groups and were similar to I-K1 in both Ba2+ sensitivity (e.g., IC50 at -120 mV: 4.5+/-1.0, 2.5+/-0.5, and 2.3+/-0.4 μM for co-injected Kir2.1/2.2, n=6, Kir-2.1/2.3, n=5, and Kir2.2/2.3, n=4, respectively) and blocking kinetics. Conclusion: Co-injection of Kir2 subunits results in currents with Ba2+ blocking properties different from homomeric Kir2 expression but similar to cardiac I-K1. These observations suggest that a substantial proportion of native I-K1, may result from heteromultimer formation among diverse Kir2 family subunits. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.