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Vol. 55, Issue 6, 993-999, June 1999
-Aminobutyric Acid Type AA Receptor Subtype-Selective
Antagonism by Furosemide
Merck Sharp & Dohme Research Laboratories, Neuroscience Research
Centre, Terlings Park, Eastwick Road, Harlow, Essex, United Kingdom
GABAA receptors in cerebellar granule cells are unique in
expressing a subtype containing the 
6 subunit. This receptor subtype has high affinity for GABA and produces a degree of tonic inhibition on
cerebellar granule cells, modulating the firing of these cells via
spillover of GABA from GABAergic synapses. This receptor subtype also
has selective affinity for the diuretic furosemide over receptors containing other -subunits. Furosemide exhibits approximately 100-fold selectivity for 6-containing receptors over 1-containing receptors. By making 1/6 chimeras we have identified a
transmembrane region (209-279) responsible for the high furosemide
sensitivity of 6
3
2s receptors. Within the 1 transmembrane
region, a single amino acid was identified that when mutated from
threonine to isoleucine, increased furosemide sensitivity by
20-fold. We demonstrate the -subunit selectivity of furosemide to be
due to asparagine 265 in the 2 and 3 transmembrane-domain
II similar to that observed with potentiation by the
anticonvulsant loreclezole. We also show that Ile in
transmembrane-domain I accounts for the increased GABA sensitivity
observed at 632s compared with 132s receptors, but
did not affect direct activation by pentobarbital or potentiation by
the benzodiazepine flunitrazepam. Location of these residues within
transmembrane domains leads to speculation that they may be involved in
the channel-gating mechanism conferring increased receptor activation
by GABA, in addition to conferring furosemide sensitivity.
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