The cardiac inward rectifier K⁺ channel subunit, CIR, does not comprise the ATP-sensitive K⁺ channel, I_KATP

Cardiac I_KACh is comprised of two inwardly rectifying K⁺ channel subunits, CIR and GIRK1 (Krapivinsky, G., Gordon, E. G., Wickman, K., Velimirovic, B., Krapivinsky, L., and Clapham, D. E. (1995) Nature 374, 135-141). A cardiac protein virtually identical to CIR, termed rcKATP-1 (Ashford, M. L. J., Bond, C. T., Blair, T. A., and Adelman, J. P. (1994) Nature 370, 456-459), was reported to form an ATP-sensitive inwardly rectifying K⁺ channel, I_KATP. We attempted to determine whether CIR alone or together with an unknown protein(s) participated in the formation of cardiac I_KATP. Expression of CIR in insect, oocyte, and mammalian cell systems did not increase the appearance of ATP-sensitive currents, but rather gave rise to unique strongly inwardly rectifying, G protein-regulated K⁺ currents. CIR protein is found exclusively in atria, in contrast to the predominance of I_KATP functional activity in ventricle. Also, CIR was completely depleted from heart membrane after immunodepletion of GIRK1. We conclude that CIR/rcKATP-1 is not a subunit of cardiac I_KATP and that GIRK1 is the only channel protein coassociating with CIR in heart.