GABAA Assays
Background of GABAA Receptors
The GABAA receptors are the major inhibitory neurotransmitter receptors in the mammalian brain. They are generally pentameric proteins composed of different subunits. The GABAA receptor is a molecular target for many clinically-used drugs, which are often used for their sedative/hypnotic and anxiolytic effects.
Fig.1 Transmitter transients and GABAA receptors at fast and slow synapses. (Capogna, 2011)
Mechanism of GABAA Receptors
GABAA receptors are members of the Cys-loop family of ligand-gated ion channels and are permeable to Cl-. Activation of these receptors leads to Cl- flow into neurons and hyperpolarization of cell membranes, making it more difficult for neurons to conduct action potentials.
The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders
Tonic inhibition is maintained in epilepsy and therefore serves as an attractive substrate for interventions. Drugs aimed at tonic GABA signaling, such as ganaxolone, show promising anticonvulsive results in rodent studies. Therefore, tonic GABAA receptors as a potential target for the treatment of temporal lobe epilepsy.
Assay List of GABAA Receptors
Creative Biolabs can provide a range of assays of GABAA receptors. You can choose the assay in the list or contact us for more information:
Published Data
| Paper Title | Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors |
| Journal | Nature |
| Published | 2022 |
| Abstract | Type A GABA (gamma-aminobutyric acid) receptors represent a distinct group in the mammalian brain. αβ receptors support extrasynaptic localization and mediate the basic persistence (tonic) inhibition of conductance in many regions of the mammalian brain. In humans, mutations in these receptors have been linked to epilepsy and insomnia. In contrast to the synaptic preferred α1βγ, α2βγ, and α3βγ receptor responses, the tonic GABaergic response is suppressed to avoid excessive inhibition of neuronal communication and shows high sensitivity to the Zn2+ blocking response. The inhibitory state of the binding of the lethal paralytic agent α-cobratoxin13 and Zn2+ was used to compare the structure of GABA-Zn2+ and GABA-bound structures. Zn2+ blocks chloride conduction by non-competitively blocking the extracellular end of the pore, thus rendering the GABA reaction ineffective. In the absence of Zn2+, the GABA signal response initially follows a canonical route until it reaches the pore. Compared to synaptic GABAA receptors, the dilatation of the mesosphere activation gate is limited and it remains closed, reflecting the inherently low efficacy of the extrasynaptic receptor. Overall, this study explains the unique characteristics adopted by αβ receptors that allow them to adapt to the role of fortitude signaling. |
| Result |
The structure presented here explains key aspects of the molecular pharmacology of the α1β3 GABA receptor, including the antagonistic mode of α-CBTx and the characteristic properties of the αβ receptor's highly sensitive Zn2+ channel blocking. Although the ECDs and M2-M3 rings respond to GABA, the more upright β-subunit M2 helix occupies the γ-subunit position, causing the 9' Leu pore gate to essentially close. This provides a molecular explanation for the lower Po of the α1β3 receptor relative to the synaptic α1β3γ2 receptor, a feature necessary to prevent excessive inhibition of neuronal circuits by the αβ and αβδ extracsynaptic isoforms. Given the recent successful therapeutic effects of targeting exsynaptic GABAA receptors, they anticipate that these structures will facilitate the future design of drugs that modulate GABA-mediated inhibition of tonic.
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Fig.2 α-Cobratoxin binding site on α1β3 GABAA receptors. (Kasaragod, 2022)
References
- Capogna, M.; Pearce, R,A. GABAA, slow: causes and consequences. Trends in neurosciences. 2011, 34(2): 101-112.
- Kasaragod, V.B.; et al. Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors. Nature. 2022, 602: 529-533.
