Brain GABA(A)/benzodiazepine receptors are highly heterogeneous. This
heterogeneity is largely derived from the existence of many pentameric
combinations of at least 16 different subunits that are differentiall
y expressed in various brain regions and cell types. This molecular he
terogeneity leads to binding differences for various ligands, such as
GABA agonists and antagonists, benzodiazepine agonists, antagonists, a
nd inverse agonists, steroids, barbiturates, ethanol, and Cl- channel
blockers. Different subunit composition also leads to heterogeneity in
the properties of the Cl- channel (such as conductance and open time)
; the allosteric interactions among subunits; and signal transduction
efficacy between ligand binding and Cl- channel opening. The study of
recombinant receptors expressed in heterologous systems has been very
useful for understanding the functional roles of the different GABA(A)
receptor subunits and the relationships between subunit composition,
ligand binding, and Cl- channel properties. Nevertheless, little is kn
own about the complete subunit composition of the native GABA(A) recep
tors expressed in various brain regions and cell types. Several labora
tories, including ours, are using subunit-specific antibodies for diss
ecting the heterogeneity and subunit composition of native (not recons
tituted) brain GABA(A) receptors and for revealing the cellular and su
bcellular distribution of these subunits in the nervous system. These
studies are also aimed at understanding the ligand-binding, transducti
on mechanisms, and channel properties of the various brain GABA(A) rec
eptors in relation to synaptic mechanisms and brain function. These st
udies could be relevant for the discovery and design of new drugs that
are selective for some GABA(A) receptors and that have fewer side eff
ects.