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Slow modal gating of single G protein‐activated K+ channels expressed in Xenopus oocytes

1 The slow kinetics of G protein‐activated K+ (GIRK) channels expressed in Xenopus oocytes were studied in single‐channel, inside‐out membrane patches. Channels formed by GIRK1 plus GIRK4 subunits, which are known to form the cardiac acetylcholine (ACh)‐activated GIRK channel (KACh), were activated by a near‐saturating dose of G protein βγ subunits (Gβγ; 20 nM). 2 The kinetic parameters of the expressed GIRK1/4 channels were similar to those of cardiac KACh. GIRK1/4 channels differed significantly from channels formed by GIRK1 with the endogenous oocyte subunit GIRK5 (GIRK1/5) in some of their kinetic parameters and in a 3‐fold lower open probability, Po. The unexpectedly low Po (0.025) of GIRK1/4 was due to the presence of closures of hundreds of milliseconds; the channel spent ∼90 % of the time in the long closed states. 3 GIRK1∼4 channels displayed a clear modal behaviour: on a time scale of tens of seconds, the Gβγ‐activated channels cycled between a low‐Po mode (Po of about 0.0034) and a bursting mode characterized by an ∼30‐fold higher Po and a different set of kinetic constants (and, therefore, a different set of channel conformations). The available evidence indicates that the slow modal transitions are not driven by binding and unbinding of Gβγ. 4 The GTPγS‐activated Gαi1 subunit, previously shown to inhibit GIRK channels, substantially increased the time spent in closed states and apparently shifted the channel to a mode similar, but not identical, to the low‐Po mode. 5 This is the first demonstration of slow modal transitions in GIRK channels. The detailed description of the slow gating kinetics of GIRK1∼4 may help in future analysis of mechanisms of GIRK gating.