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Interaction of G Protein Subunit with Inward Rectifier K⁺ Channel Kir3

Departments of Pharmacology (Q.Z., H.N, S.N., T.Ko.) and Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Illinois 60612 (T.Ka., Y.N.)

G protein subunits bind and activate G protein-coupled inward rectifier K⁺ (GIRK) channels. This protein-protein interaction is crucial for slow hyperpolarizations of cardiac myocytes and neurons. The crystal structure of G shows a seven-bladed propeller with four strands in each blade. The G/G interacting surface contains sites for activating GIRK channels. Furthermore, our recent investigation using chimeras between G₁ and yeast (STE4) suggested that the outer strands of blades 1 and 2 of G1 could be an interaction area between G1 and GIRK. In this study, we made point mutations on suspected residues on these outer strands and investigated their ability to activate GIRK1/GIRK2 channels. Mutations at Thr-86, Thr-87, and Gly-131, all located on the loops between -strands, substantially reduced GIRK channel activation, suggesting that these residues are G/GIRK interaction sites. These mutations did not affect the expression of G1 or its ability to stimulate PLC2. These residues are surface-accessible and located outside G/G interaction sites. These results suggest that the residues on the outer surface of blades 1 and 2 are involved in the interaction of G with GIRK channels. Our study suggests a mechanism by which different effectors use different blades to achieve divergence of signaling. We also observed that substitution of alanine for Trp-332 of G1 impaired the functional interaction of G1 with GIRK, in agreement with the data on native neuronal GIRK channels. Trp-332 plays a critical role in the interaction of G1 with G as well as all effectors so far tested.

Address correspondence to: Tohru Kozasa, Department of Pharmacology, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612. E-mail: tkozas{at}uic.edu

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