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Biophys J, February 2001, p. 707-718, Vol. 80, No. 2
The Salk Institute for Biological Studies, Peptide Biology Lab, La Jolla, California 92037 USA
The weaver mutation (G156S) in
G-protein-gated inwardly rectifying K+ (GIRK) channels
alters ion selectivity and reveals sensitivity to inhibition by a
charged local anesthetic, QX-314, applied extracellularly. In this
paper, disrupting the ion selectivity in another GIRK channel, chimera
I1G1(M), generates a GIRK channel that is also inhibited by
extracellular local anesthetics. I1G1(M) is a chimera of IRK1
(G-protein-insensitive) and GIRK1 and contains the hydrophobic domains
(M1-pore-loop-M2) of GIRK1 (G1(M)) with the N- and C-terminal domains
of IRK1 (I1). The local anesthetic binding site in I1G1(M) is
indistinguishable from that in GIRK2wv channels. Whereas
chimera I1G1(M) loses K+ selectivity, although there are no
mutations in the pore-loop complex, chimera I1G2(M), which contains the
hydrophobic domain from GIRK2, exhibits normal K+
selectivity. Mutation of two amino acids that are unique in the pore-loop complex of GIRK1 (F137S and A143T) restores K+
selectivity and eliminates the inhibition by extracellular local anesthetics, suggesting that the pore-loop complex prevents QX-314 from
reaching the intrapore site. Alanine mutations in the extracellular half of the M2 transmembrane domain alter QX-314 inhibition, indicating the M2 forms part of the intrapore binding site. Finally, the inhibition of G-protein-activated currents by intracellular QX-314 appears to be different from that observed in nonselective GIRK channels. The results suggest that inward rectifiers contain an intrapore-binding site for local anesthetic that is normally
inaccessible from extracellular charged local anesthetics.
Biophys J, February 2001, p. 707-718, Vol. 80, No. 2
© 2001 by the Biophysical Society 0006-3495/01/02/707/12 $2.00
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