γ-Aminobutyric acid can be deactivated and recycled by the transamination reaction
withα-ketoglutarate to yield glutamate. This reaction circumvents the usual oxidative
route, insofar as glutamate can be decarboxylated to yield GABA once again. This
transamination is catalyzed by the enzyme GABA transaminase (GABA-T), which is
widely distributed. Therefore, free GABA cannot be found anywhere except in the
brain. The transaminase enzyme also depends on pyridoxal phosphate as a cofactor.
4.7.2 Characterization of GABAergic ReceptorsGABAergic receptors have been investigated extensively over the past 20 years. The
great increase in research activity in this area was largely due to the recognition that the
extremely widely used benzodiazepine tranquilizers (e.g., diazepam, Valium) act
through the GABA receptor. Currently three major GABA receptors are recognized:
GABAA, GABAB, and GABAC.
The GABAAreceptor was first cloned using partial protein sequence followed by
cDNA expression of GABA-activated channels in Xenopusoocytes. The GABAArecep-
tor is an ionophore complex; it is a 275 kDa heteropentameric glycoprotein composed
of five different subunit peptides selected from a group of at least 19 different but
closely related polypeptides. These subunit peptides are divided into six classes:α,β,
γ,δ,ε, and ρ. There are 6 subtypes of the α subunit, 4 subtypes of the β subunit, 4 sub-
types of the γ subunit, and 3 subtypes of the ρ subunit. There is 30% sequence homol-
ogy between subunit peptides and 70% sequence homology within a subunit class.
A typical GABAAreceptor could consist of two α subunits, two β subunits, and a
γ subunit to yield the pentameric structure. However, an array of other compositions is
possible, depending upon which subunit proteins are used. Different combinations of
subunits with differing pharmacologies and conductances are expressed in different
areas of the brain. Each GABAAsubunit contains four α-helical membrane-spanning
domains (M1–M4). A membrane-spanning region from each of the M2 domains from
each of the pentameric subunits forms the walls of a central ion channel pore. The seg-
ment between M3 and M4 within each subunit is a long variable intracellular domain
that contributes to receptor specificity in regulating intracellular mechanisms. The
GABAAreceptor is a member of a superfamily of ligand-gated ion channel receptors,
which also includes the acetylcholine receptor and the 5-HT 3 serotonin receptor.
Less is known about GABABreceptor structure. GABABreceptors are coupled indi-
rectly to K+channels. These receptors, which are always inhibitory, are coupled to
G-proteins. When activated, GABABreceptors decrease Ca^2 +conductance and inhibit
cAMP production. The GABACreceptor is probably little more than a subtype of the
GABAAreceptor. It contains the ρsubunit peptide and is located primarily, if not
exclusively, in the retina.
The neuronal activity of GABA shows different inhibitory mechanisms reflecting the
GABAAand GABABreceptors. The first mechanism is the conventional hyperpolariza-
tion of an excitatory neuron by increased Cl−ion flux, which makes the neuron unable
to fire when it receives a normal impulse. The second is the partial (presynaptic) depo-
larization of an excitatory neuron, which causes a decrease in neurotransmitter release
when this neuron receives an electrical impulse.
NEUROTRANSMITTERS AND THEIR RECEPTORS 271