English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Commentary In adult mammalian neurons, ionotropic GABAA receptors function as inhibitory channels, facilitating the entry of nega­ tively charged chloride ions into the cell. This inhibitory effect occurs in the presence of GABA—the endogenous ligand for GABAA receptors, and also other molecules, such as neuro­ steroids, which act as positive allosteric modulators. GABAA receptors are pentameric structures comprising a mixture of subunit proteins (to date including α1­6, β1­3, g1­3, δ, ε, θ, π, ρ1­3 proteins) that form a central ion channel. This impres­ sive diversity results in a vast array of potential combinations of receptor species, each with different functional properties, cell­surface distributions, and regional expression patterns within the brain. GABAA receptors containing a δ subunit are primarily located extrasynaptically, where they mediate a tonic form of inhibition, which is temporally unrelated to phasic synaptic events (1). GABA­mediated tonic conductance (Itonic) has been identified in several brain regions, notably the den­ tate gyrus (2), where it modulates network excitability in the hippocampus. Given the function and the regional location of these receptors, it is not surprising that they have been closely linked with epilepsy: antagonists of GABAA receptors, such as bicuculline, promote seizures, whereas activators of these receptors, such as diazepam and stiripentol (3), are used clini­ cally as antiseizure agents. In addition, mutations in Gabrd, the gene coding for the δ subunit of the GABAA receptor, appear to contribute to epilepsy susceptibility (4). Neuroactive steroids, or neuro steroids, act as positive al­ losteric modulators of GABAA receptors, potently enhancing the inhibitory effects of GABA (5). While a detailed understand­ ing of how these molecules interact with GABAA receptors to modulate channel function has been generated for synaptic g­containing receptors (6), structure­activity relationships of neuro steroids acting at extrasynaptic receptors has not been established. This represents critical missing information, since δ­subunit–containing GABAA receptors appear preferentially sensitive to physiological GABA concentrations (7), and neuro­ steroids exhibit reduced tonic current and decreased sensitivity in δ­subunit knock­out (δKO) mice (8). The authors therefore set out to confirm the influence of the δ­subunit of GABAA recep­ tors for GABA­mediated tonic current, and to characterize the structure­activity relationship and functional consequences of neuro steroids acting at δ­containing GABAA receptors on Itonic. Neurosteroid Structure-Activity Relationships for Functional Activation of Extrasynaptic GABAA Receptors.

Potentiating the Strength of Extrasynaptic Currents by Neurosteroid Hormones