CONTROL OF CHANNEL ACTIVITY THROUGH A UNIQUE AMINO-ACID RESIDUE OF A G-PROTEIN-GATED INWARDLY RECTIFYING K+ CHANNEL SUBUNIT

G protein-gated inwardly rectifying K+ (GIRK) channels,,which are impo rtant regulators of membrane excitability both in heart and brain, app ear to function as heteromultimers. GIRK1 is unique in the GIRK channe l family in that although it is by itself inactive, it can associate w ith the other family members (GIRK2-GIRK5) to enhance their activity a nd alter their single-channel characteristics. By generating a series of chimeras, we identified a phenylalanine residue, F137, in the pore region of GIRK1 that critically controls channel activity, F137 is fou nd only in GIRK1, while the remaining GIRK channels possess a conserve d serine residue in the analogous position. The single-point mutant GI RK4(S143F) behaved as a GIRK1 analog, forming multimers with GIRK2, GI RK4, or GIRK5 channels that exhibited prolonged single-channel open-ti me duration and enhanced activity compared with that of homomultimers. Expression of the corresponding GIRK1(F137S) mutant alone resulted in appreciable channel activity with novel characteristics that was furt her enhanced upon coexpression with other GIRK subunits. Thus, althoug h the F137 residue renders the GIRK1 subunit inactive, when combined w ith other GIRK heteromeric partners it alters their gating and contrib utes to their enhanced activity.