Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes

Abstract

GABAA receptors are a family of ligand-gated ion channels which are essential for the regulation of central nervous system function. Benzodiazepines – which target GABAA receptors containing the α1, α2, α3, or α5 subunits non-selectively – have been in clinical use for decades and are still among the most widely prescribed drugs for the treatment of insomnia and anxiety disorders. However, their use is limited by side effects and the risk of drug dependence. In the past decade, the identification of separable key functions of GABAA receptor subtypes suggests that receptor subtype-selective compounds could overcome the limitations of classical benzodiazepines and, furthermore, might be valuable for novel indications, such as analgesia, depression, schizophrenia, cognitive enhancement and stroke.

Transcriptional control ofGad2

“…Both animal research and clinical studies have established that perturbation of the GABA inhibitory system is involved in the pathogenesis of a variety of neurological diseases, including epilepsy, schizophrenia, depression, anxiety and chronic pain. [31][32][33] Most of these previous studies focused on the post-synaptic GABA A receptor of GABA synapses as potential therapeutic targets for the treatment of these pathological conditions. However, given the activity-dependent GAD65 function and particularly, activity-regulated Gad2 expression through epigenetic control of transcription, Gad2 might play a more important role in the chronic disease condition-induced plasticity of central GABA synapses.…”

Reinforcing Effects Of Compounds Lacking Intrinsic Efficacy At α1 Subunit-Containing GABAA Receptor Subtypes in Midazolam- But Not Cocaine-Experienced Rhesus Monkeys

“…Benzodiazepines potentiate the effects of the neurotransmitter g-aminobutyric acid (GABA) via positive allosteric modulation at the g-aminobutyric acid type A (GABA A ) receptor. GABA A receptors are heteropentameric chloride ion channels assembled in a typical stoichiometry of 2 a, 2 b, and 1 g subunits; conventional benzodiazepines bind to GABA A receptors containing a1, a2, a3, or a5 subunits (a1GABA A , a2GABA A , a3GABA A , or a5GABA A receptors, respectively; Rudolph and Knoflach, 2011;Tan et al, 2011). Previous studies have shown localization of a1GABA A receptors on inhibitory interneurons that synapse with DA neurons in the ventral tegmental area (VTA; Heikkinen et al, 2009;Tan et al, 2010) while a3GABA A receptors are expressed at lower levels on the DA neurons themselves (Fritschy and Mohler, 1995;Ciccarelli et al, 2012).…”

Structural and Functional Studies of the Modulator NS9283 Reveal Agonist-like Mechanism of Action at α4β2 Nicotinic Acetylcholine Receptors

“…Etomidate binds to sites in the transmembrane region of the receptor where it modulates GABA A R efficacy levels at low concentrations and directly activates at high concentrations, similarly to the barbiturate type of modulators at this receptor (12,13). In contrast, benzodiazepines only modulate the GABA potency and are known to bind in an extracellular pocket in the receptor ␣-␥ interface, a pocket that is structurally similar to the GABA-binding ␤-␣-subunit pocket (6,9).…”

“…Both receptor types are implicated as either cause or remedy in devastating diseases, including anxiety, Parkinson, and Alzheimer diseases, pain, and attention deficit hyperactivity disorder (3)(4)(5). Therefore, the development of drugs that target these receptors is a priority area for research (3,6). Although allosteric modulators are mechanistically less well understood than agonists, they are believed to have advantages as pharmaceuticals.…”