Rm. Mckernan et al., THE PHARMACOLOGY OF THE BENZODIAZEPINE SITE OF THE GABA-A RECEPTOR ISDEPENDENT ON THE TYPE OF GAMMA-SUBUNIT PRESENT, Journal of receptor and signal transduction research, 15(1-4), 1995, pp. 173-183
The pharmacology of native and recombinant GABA-A receptors containing
either gamma 1,gamma 2 or gamma 3 subunits has been investigated. The
pharmacology of native receptors has been investigated by immunopreci
pitating receptors form solubilised preparations of rat brain with ant
isera for individual gamma-subunits and analysing their radioligand bi
nding characteristics. Receptors containing a gamma 1-subunit do not b
ind benzodiazepine radioligands with high affinity. Those containing e
ither a gamma 2 or gamma 3 subunit bind [H-3]flumazenil with high affi
nity. Some compounds compete for these binding sites with multiple aff
inities, reflecting the presence of populations of receptors containin
g several different types of alpha-subunit. Photoaffinity-labelling of
GABA-A receptors from a cell line stably expressing GABA-A receptors
of composition alpha 1 beta 3 gamma 2 followed by immunoprecipitation
of individual subunits revealed that the alpha and gamma but not the b
eta-subunit could be irreversibly labelled by [H-3]flunitrazepam. The
properties of recombinant receptors have been investigated in oocytes
expressing gamma 1,gamma 2, or gamma 3 subunits in combination with an
alpha and a beta-subunit. Some compounds such as zolpidem, DMCM and f
lunitrazepam show selectivity for receptors containing different gamma
-subunits. Others such as Cl 218,872 show no selectivity between recep
tors containing different alpha-subunits. These data taken together su
ggest that the benzodiazepine site of the GABA-A receptor is formed wi
th contributions from both the alpha and gamma-subunits.