The maximal drug effect varies with the operational configuration of the GABAergic synapse. The number of receptors or the concentration of GABA in the synaptic cleft can differ between synapses. If the release of a single quantum of GABA is able to saturate all the GABAA receptors, the GABA – induced peak response is not enhanced, or only minimally, in the presence
of benzodiazepines. In a synapse that operates under nonsaturating conditions, the drug-induced increase in the affinity of the receptor for GABA results in the recruitment of more receptors for activation by GABA. Thus, benzodiazepine drugs become Inhibitors,research,lifescience,medical most strongly effective when the GABAergic operation of the synapse is submaximal.36,37 Figure 3. Scheme of a GABAergic synapse depicting the major elements of signal transduction. The ionotropic GABA,. receptors are heteromeric membrane proteins linked in a yet unknown, indirect Inhibitors,research,lifescience,medical way to the synaptic anchoring protein gephyrin and the cytoskeleton. … GABAA receptors and their multiplicity On the basis of the presence of 7 subunit families comprising at least 18 subunits in the CNS (α1-6, β 1-3, γ1-3, δ, ε, θ, and ρ1-3), the pentameric GABAA receptors display an extraordinary structural heterogeneity. .Most GABAA receptors subtypes in vivo are believed to be composed of a, p Inhibitors,research,lifescience,medical and y subunits. The physiological Depsipeptide significance of the structural diversity of GABAA receptors lies in the provision of receptors that differ in
their channel kinetics, affinity for GABA, rate of desensitization, and subcellular positioning.24 For instance, synaptic and extrasynaptic GABAA receptors differ kinetically. Extrasynaptic GABAA receptors containing the δ subunit in dentate gyrus and
Inhibitors,research,lifescience,medical cerebellum are tailor-made for tonic inhibition, due to their high affinity for GABA and slow Inhibitors,research,lifescience,medical desensitization kinetics.38,39 Marked differences in desensitization kinetics have also been reported for synaptic and extrasynaptic receptors in inferior olivary neurons.40 Further insights into the heterogeneity of GABAA receptors is expected to arise from the identification of receptor-associated proteins and their regulation.41 Diazepam-sensitive GABAA receptors Functionally, GABAA receptors are best distinguished by many their pharmacology. Receptors containing the α1, α2, α3 or α5 subunits in combination with any of the β subunits and the γ2 subunit are benzodiazepine sensitive. These receptors represent about 90% of all GABAA receptors with the major receptor subtype being assembled from the subunits α1β 2γ2 Only a few brain regions lack this receptor (Table I):42,44 Table I GABAA (γ-aminobutyric acid) receptor subtypes. Modified from reference 35: Möhler H, Frifschy JM. Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002;300:2-8. Copyrighf © 2002, American Sociefy for Pharmacology … Receptors containing the α2 or α3 subunit are less abundant and are highly expressed in brain areas where the α1 subunit is absent or present at low levels.