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J. Biol. Chem., Vol. 277, Issue 48, 46166-46171, November 29, 2002
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From the Department of Biology, Georgia State University, Atlanta,
Georgia 30302-4010
Synaptic cleft acidification occurs following
vesicle release. Such a pH change may affect synaptic transmissions in
which G-protein-coupled inward rectifier K+ (GIRK)
channels play a role. To elucidate the effect of extracellular pH
(pHo) on GIRK channels, we performed experiments on heteromeric
GIRK1/GIRK4 channels expressed in Xenopus oocytes. A
decrease in pHo to 6.2 augmented GIRK1/GIRK4 currents by
~30%. The channel activation was reversible and dependent on pHo levels. This effect was produced by selective augmentation of single channel conductance without change in the open-state probability. To determine which subunit was involved, we took advantage
of homomeric expression of GIRK1 and GIRK4 by introducing a single
mutation. We found that homomeric GIRK1-F137S and GIRK4-S143T channels
were activated at pHo 6.2 by ~20 and ~70%, respectively. Such activation was eliminated when a histidine residue in the M1-H5
linker was mutated to a non-titratable glutamine, i.e.
H116Q in GIRK1 and H120Q in GIRK4. Both of these histidines were
required for pH sensing of the heteromeric channels, because the
mutation of one of them diminished but not abolished the pHo
sensitivity. The pHo sensitivity of the heteromeric channels
was completely lost when both were mutated. Thus, these results suggest
that the GIRK-mediated synaptic transmission is determined by both neurotransmitter and protons with the transmitter accounting for only
70% of the effect on postsynaptic cell and protons released together
with the transmitter contributing to the other
30%.
Molecular Determinants for Activation of G-protein-coupled Inward
Rectifier K+ (GIRK) Channels by Extracellular
Acidosis*
*
This work was supported by the National Institutes of Health
Grant HL58410 and the American Diabetes Association Grant 1-01-RA-12.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Career Investigator of the American Lung Association. To
whom correspondence should be addressed: Dept. of Biology, Georgia State University, 24 Peachtree Center Ave., Atlanta, Georgia
30302-4010. Tel.: 404-651-0913; Fax: 404-651-2509; E-mail:
cjiang@gsu.edu.
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