GABAA receptor

Structure of the GABAA receptor (α1β1γ2S: PDB: 6DW1). Top: side view of the GABAA receptor embedded in a cell membrane. Bottom: view of the receptor from the extracellular face of the membrane. The subunits are labeled according to the GABAA nomenclature and the approximate locations of the GABA and benzodiazepine (BZ) binding sites are noted (between the α- and β-subunits and between the α- and γ-subunits respectively).
Schematic structure of the GABAA receptor. Left: GABAA monomeric subunit embedded in a lipid bilayer (yellow lines connected to blue spheres). The four transmembrane α-helices (1–4) are depicted as cylinders. The disulfide bond in the N-terminal extracellular domain which is characteristic of the family of cys-loop receptors (which includes the GABAA receptor) is depicted as a yellow line. Right: Five subunits symmetrically arranged about the central chloride anion conduction pore. The extracellular loops are not depicted for the sake of clarity.

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS).[1] Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl−
) and, to a lesser extent, bicarbonate ions (HCO−
3).[2][3]

GABAAR are members of the ligand-gated ion channel receptor superfamily, which is a chloride channel family with a dozen or more heterotetrametric subtypes and 19 distinct subunits. These subtypes have distinct brain regional and subcellular localization, age-dependent expression, and the ability to undergo plastic alterations in response to experience, including drug exposure.[4]

GABAAR is not just the target of agonist depressants and antagonist convulsants, but most GABAAR medicines also act at additional (allosteric) binding sites on GABAAR proteins. Some sedatives and anxiolytics, such as benzodiazepines and related medicines, act on GABAAR subtype-dependent extracellular domain sites. Alcohols and neurosteroids, among other general anesthetics, act at GABAAR subunit-interface transmembrane locations. High anesthetic dosages of ethanol act on GABAAR subtype-dependent transmembrane domain locations. Ethanol acts at GABAAR subtype-dependent extracellular domain locations at low intoxication concentrations. Thus, GABAAR subtypes have pharmacologically distinct receptor binding sites for a diverse range of therapeutically significant neuropharmacological drugs.[4]

Depending on the membrane potential and the ionic concentration difference, this can result in ionic fluxes across the pore. If the membrane potential is higher than the equilibrium potential (also known as the reversal potential) for chloride ions, when the receptor is activated Cl−
 will flow into the cell.[5] This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring at the postsynaptic cell. The reversal potential of the GABAA-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABAB IPSP (−100 mV).

The active site of the GABAA receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline.[6] The protein also contains a number of different allosteric binding sites which modulate the activity of the receptor indirectly. These allosteric sites are the targets of various other drugs, including the benzodiazepines, nonbenzodiazepines, neuroactive steroids, barbiturates, alcohol (ethanol),[7] inhaled anaesthetics, kavalactones, cicutoxin, and picrotoxin, among others.[8]

Much like the GABAA receptor, the GABAB receptor is an obligatory heterodimer consisting of GABAB1 and GABAB2 subunits. These subunits include an extracellular Venus Flytrap domain (VFT) and a transmembrane domain containing seven α-helices (7TM domain). These structural components play a vital role in intricately modulating neurotransmission and interactions with drugs. [9]

  1. ^ Luscher B, Fuchs T, Kilpatrick CL (May 2011). "GABAA receptor trafficking-mediated plasticity of inhibitory synapses". Neuron. 70 (3): 385–409. doi:10.1016/j.neuron.2011.03.024. PMC 3093971. PMID 21555068.
  2. ^ Folkman, Susan. (2011). The Oxford handbook of stress, health, and coping. Oxford: Oxford University Press. ISBN 978-0-19-537534-3. OCLC 540015689.
  3. ^ Kaila K, Voipio J (18 November 1987). "Postsynaptic fall in intracellular pH induced by GABA-activated bicarbonate conductance". Nature. 330 (6144): 163–5. Bibcode:1987Natur.330..163K. doi:10.1038/330163a0. PMID 3670401. S2CID 4330077.
  4. ^ a b Olsen RW (July 2018). "GABAA receptor: Positive and negative allosteric modulators". Neuropharmacology. 136 (Pt A): 10–22. doi:10.1016/j.neuropharm.2018.01.036. PMC 6027637. PMID 29407219.
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  6. ^ Chua HC, Chebib M (2017). "GABA a Receptors and the Diversity in their Structure and Pharmacology". GABAA Receptors and the Diversity in their Structure and Pharmacology. Advances in Pharmacology. Vol. 79. pp. 1–34. doi:10.1016/bs.apha.2017.03.003. ISBN 978-0-12-810413-2. PMID 28528665. S2CID 41704867.
  7. ^ Santhakumar V, Wallner M, Otis TS (May 2007). "Ethanol acts directly on extrasynaptic subtypes of GABAA receptors to increase tonic inhibition". Alcohol. 41 (3): 211–221. doi:10.1016/j.alcohol.2007.04.011. PMC 2040048. PMID 17591544.
  8. ^ Johnston GA (1996). "GABAA receptor pharmacology". Pharmacology & Therapeutics. 69 (3): 173–198. doi:10.1016/0163-7258(95)02043-8. PMID 8783370.
  9. ^ Evenseth LS, Gabrielsen M, Sylte I (July 2020). "The GABAB Receptor-Structure, Ligand Binding and Drug Development". Molecules. 25 (13): 3093. doi:10.3390/molecules25133093. PMC 7411975. PMID 32646032.