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The Journal of Neuroscience, April 15, 1998, 18(8):2944-2953
The Role of an  Subtype M2-M3 His in
Regulating Inhibition of GABAA Receptor Current by Zinc and
Other Divalent Cations
Janet L.
Fisher1 and
Robert L.
Macdonald1, 2
1 Departments of Neurology and
2 Physiology, University of Michigan, Ann Arbor, Michigan
48104-1687
Sensitivity of GABAA receptors (GABARs) to inhibition
by zinc and other divalent cations is influenced by the  subunit
subtype composition of the receptor. For example, 6 3 2L
receptors are more sensitive to inhibition by zinc than 132L
receptors. We examined the role of a His residue located in the
M2-M3 extracellular domain (rat 6 H273) in
the enhanced zinc sensitivity conferred by the 6 subtype. The 1
subtype contains an Asn (N274) residue in the equivalent location.
GABA-activated whole-cell currents were obtained from L929 fibroblasts
after transient transfection with expression vectors containing
GABAA receptor cDNAs. Mutation of 1
(1(N274H)) or 6 (6(H273N)) subtypes
did not alter the GABA EC50 of 32L receptors.
1(N274H)32L receptor currents were as sensitive to
zinc as 632L receptor currents, although 6(H273N)32L receptor currents had the reduced zinc
sensitivity of 132L receptor currents. We also examined the
activity of other inhibitory divalent cations with varying subtype
dependence: nickel, cadmium, and copper. 632L receptor
currents were more sensitive to nickel, equally sensitive to cadmium,
and less sensitive to copper than 132L receptor currents.
Studies with 1 and 6 chimeric subunits indicated that the
structural dependencies of the activity of some of these cations were
different from zinc. Compared with 632L receptor currents,
6(H273N)32L receptor currents had reduced
sensitivity to cadmium and nickel, but the sensitivity to copper was
unchanged. Compared with 132L receptor currents,
1(N274H)32L receptor currents had increased
sensitivity to nickel, but the sensitivity to cadmium and copper was
unchanged. These findings indicate that H273 of the 6 subtype plays
an important role in determining the sensitivity of recombinant GABARs
to the divalent cations zinc, cadmium, and nickel, but not to copper. Our results also suggest that the extracellular N-terminal domain of
the 1 subunit contributes to a regulatory site(s) for divalent cations, conferring high sensitivity to inhibition by copper and cadmium.
Key words:
GABA; divalent cations; GABA receptor; zinc; cadmium; copper; nickel; recombinant; site-directed mutagenesis;
Copyright © 1998 Society for Neuroscience 0270-6474/98/1882944-10$05.00/0
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