GABAA receptor

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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).
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

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 (HCO3).[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.[5]

Depending on the

equilibrium potential (also known as the reversal potential) for chloride ions, when the receptor is activated Cl will flow into the cell.[6] 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

kavalactones, cicutoxin, and picrotoxin, among others.[9]

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. [10]

Target for benzodiazepines

The

GABA (whose binding site is located between α- and β-subunits), but bind to distinct benzodiazepine binding sites situated at the interface between the α- and γ-subunits of α- and γ-subunit containing GABAA receptors.[11][12] While the majority of GABAA receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive, there exists a minority of GABAA receptors (α4- or α6-subunit containing) which are insensitive to classical 1,4-benzodiazepines,[13] but instead are sensitive to other classes of GABAergic drugs such as neurosteroids and alcohol. In addition peripheral benzodiazepine receptors exist which are not associated with GABAA receptors. As a result, the IUPHAR has recommended that the terms "BZ receptor", "GABA/BZ receptor" and "omega receptor" no longer be used and that the term "benzodiazepine receptor" be replaced with "benzodiazepine site".[14] Benzodiazepines like diazepam and midazolam act as positive allosteric modulators for GABAA receptors. When these receptors are activated, there's a rise in intracellular chloride levels, resulting in cell membrane hyperpolarization and decreased excitation.[15]

In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, between which the benzodiazepine binds. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarising the membrane. This potentiates the inhibitory effect of the available GABA leading to sedative and anxiolytic effects.[16]

Different benzodiazepines have different affinities for GABAA receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. For instance, benzodiazepine receptor ligands with high activity at the α1 and/or α5 tend to be more associated with sedation, ataxia and amnesia, whereas those with higher activity at GABAA receptors containing α2 and/or α3 subunits generally have greater anxiolytic activity.[17] Anticonvulsant effects can be produced by agonists acting at any of the GABAA subtypes, but current research in this area is focused mainly on producing α2-selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia.

The binding site for benzodiazepines is distinct from the binding site for

barbiturates and GABA on the GABAA receptor, and also produces different effects on binding,[18] with the benzodiazepines increasing the frequency of the chloride channel opening, while barbiturates increase the duration of chloride channel opening when GABA is bound.[19] Since these are separate modulatory effects, they can both take place at the same time, and so the combination of benzodiazepines with barbiturates is strongly synergistic, and can be dangerous if dosage is not strictly controlled.[20]

Also note that some GABAA agonists such as muscimol and gaboxadol do bind to the same site on the GABAA receptor complex as GABA itself, and consequently produce effects which are similar but not identical to those of positive allosteric modulators like benzodiazepines.

Structure and function

Schematic diagram of a GABAA receptor protein ((α1)2(β2)2(γ2)) which illustrates the five combined subunits that form the protein, the chloride (Cl) ion channel pore, the two GABA active binding sites at the α1 and β2 interfaces, and the benzodiazepine (BZD) allosteric binding site[21]

Structural understanding of the GABAA receptor was initially based on homology models, obtained using crystal structures of homologous proteins like Acetylcholine binding protein (AChBP) and nicotinic acetylcholine (nACh) receptors as templates.[22][23][24] The much sought structure of a GABAA receptor was finally resolved, with the disclosure of the crystal structure of human β3 homopentameric GABAA receptor.[25] Whilst this was a major development, the majority of GABAA receptors are heteromeric and the structure did not provide any details of the benzodiazepine binding site. This was finally elucidated in 2018 by the publication of a high resolution cryo-EM structure of rat α1β1γ2S receptor[26] and human α1β2γ2 receptor bound with GABA and the neutral benzodiazepine flumazenil.[27]

GABAA receptors are

pore. Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. The receptor sits in the membrane of its neuron, usually localized at a synapse, postsynaptically. However, some isoforms may be found extrasynaptically.[28] When vesicles of GABA are released presynaptically and activate the GABA receptors at the synapse, this is known as phasic inhibition. However, the GABA escaping from the synaptic cleft can activate receptors on presynaptic terminals or at neighbouring synapses on the same or adjacent neurons (a phenomenon termed 'spillover') in addition to the constant, low GABA concentrations in the extracellular space results in persistent activation of the GABAA receptors known as tonic inhibition.[29]

The

The endogenous ligand that binds to the benzodiazepine site is inosine.[35]

Proper developmental, neuronal cell-type-specific, and activity-dependent GABAergic transmission control is required for nearly all aspects of CNS function.[36]

It has been proposed that the GABAergic system is disrupted in numerous neurodevelopmental diseases, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and that it is a crucial potential target for therapeutic intervention.[37]

Subunits

GABAA receptors are members of the large pentameric ligand gated ion channel (previously referred to as "Cys-loop" receptors) super-family of evolutionarily related and structurally similar

isoforms for the GABAA receptor, which determine the receptor's agonist affinity, chance of opening, conductance, and other properties.[38]

In humans, the units are as follows:

There are three ρ units (GABRR1, GABRR2, GABRR3); however, these do not coassemble with the classical GABAA units listed above,[39] but rather homooligomerize to form GABAA-ρ receptors (formerly classified as GABAC receptors but now this nomenclature has been deprecated[40]).

Combinatorial arrays

Given the large number of GABAA receptors, a great diversity of final pentameric receptor subtypes is possible. Methods to produce cell-based laboratory access to a greater number of possible GABAA receptor subunit combinations allow teasing apart of the contribution of specific receptor subtypes and their physiological and pathophysiological function and role in the CNS and in disease.[41]

Distribution

GABAA receptors are responsible for most of the physiological activities of GABA in the central nervous system, and the receptor subtypes vary significantly. Subunit composition can vary widely between regions and subtypes may be associated with specific functions. The minimal requirement to produce a GABA-gated ion channel is the inclusion of an α and a β subunit.

malignancies, as GABAA receptors can influence cell proliferation.[45]

Distribution of Receptor Types[46]
Isoform Synaptic/Extrasynaptic Anatomical location
α1β3γ2S Both Widespread
α2β3γ2S Both Widespread
α3β3γ2S Both Reticular thalamic nucleus
α4β3γ2S Both Thalamic relay cells
α5β3γ2S Both Hippocampal pyramidal cells
α6β3γ2S Both Cerebellar granule cells
α1β2γ2S Both Widespread, most abundant
α4β3δ Extrasynaptic Thalamic relay cells
α6β3δ Extrasynaptic Cerebellar granule cells
α1β2 Extrasynaptic Widespread
α1β3 Extrasynaptic Thalamus, hypothalamus
α1β2δ Extrasynaptic Hippocampus
α4β2δ Extrasynaptic Hippocampus, Prefrontal cortex
α3β3θ Extrasynaptic Hypothalamus
α3β3ε Extrasynaptic Hypothalamus

Ligands

GABAA receptor and where various ligands bind.

A number of

which?
] A ligand can possess one or more properties of the following types. Unfortunately the literature often does not distinguish these types properly.

Types

  • Orthosteric agonists and antagonists: bind to the main receptor site (the site where GABA normally binds, also referred to as the "active" or "orthosteric" site). Agonists activate the receptor, resulting in increased Cl conductance. Antagonists, though they have no effect on their own, compete with GABA for binding and thereby inhibit its action, resulting in decreased Cl conductance.
  • First order allosteric modulators: bind to allosteric sites on the receptor complex and affect it either in a positive (PAM), negative (NAM) or neutral/silent (SAM) manner, causing increased or decreased efficiency of the main site and therefore an indirect increase or decrease in Cl conductance. SAMs do not affect the conductance, but occupy the binding site.
  • Second order modulators: bind to an allosteric site on the receptor complex and modulate the effect of first order modulators.
  • Open channel blockers: prolong ligand-receptor occupancy, activation kinetics and Cl ion flux in a subunit configuration-dependent and sensitization-state dependent manner.[47]
  • Non-competitive channel blockers: bind to or near the central pore of the receptor complex and directly block Cl conductance through the ion channel.

Examples

Effects

Ligands which contribute to receptor activation typically have

hallucinogenic.[citation needed] Ligands which decrease receptor activation usually have opposite effects, including anxiogenesis and convulsion.[citation needed] Some of the subtype-selective negative allosteric modulators such as α5IA are being investigated for their nootropic effects, as well as treatments for the unwanted side effects of other GABAergic drugs.[59] Advances in molecular pharmacology and genetic manipulation of rat genes have revealed that distinct subtypes of the GABAA receptor mediate certain parts of the anaesthetic behavioral repertoire.[60]

Novel drugs

A useful property of the many benzodiazepine site allosteric modulators is that they may display selective binding to particular subsets of receptors comprising specific subunits. This allows one to determine which GABAA receptor subunit combinations are prevalent in particular brain areas and provides a clue as to which subunit combinations may be responsible for behavioral effects of drugs acting at GABAA receptors. These selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic effects from undesirable side effects.[61] Few subtype selective ligands have gone into clinical use as yet, with the exception of zolpidem which is reasonably selective for α1, but several more selective compounds are in development such as the α3-selective drug adipiplon. There are many examples of subtype-selective compounds which are widely used in scientific research, including:

Diazepam is a benzodiazepine medication that is FDA approved for the treatment of anxiety disorders, the short-term relief of anxiety symptoms, spasticity associated with upper motor neuron disorders, adjunct therapy for muscle spasms, preoperative anxiety relief, the management of certain refractory epileptic patients, and as an adjunct in severe recurrent convulsive seizures and status epilepticus.[62]

Paradoxical reactions

There are multiple indications that paradoxical reactions upon — for example — benzodiazepines, barbiturates, inhalational anesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABAA receptors. The combination of the five subunits of the receptor (see images above) can be altered in such a way that for example the receptor's response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one.

There are estimates that about 2–3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.[64][65][66][67]

See also

References

  1. ^ Luscher B, Fuchs T, Kilpatrick CL. GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron. 2011 May 12;70(3):385-409. doi: 10.1016/j.neuron.2011.03.024. PMID: 21555068; PMCID: PMC3093971.
  2. OCLC 540015689.{{cite book}}: CS1 maint: others (link
    )
  3. .
  4. ^ Olsen RW. GABAA receptor: Positive and negative allosteric modulators. Neuropharmacology. 2018 Jul 1;136(Pt A):10-22. doi: 10.1016/j.neuropharm.2018.01.036. Epub 2018 Jan 31. PMID: 29407219; PMCID: PMC6027637.
  5. ^ Olsen RW. GABAA receptor: Positive and negative allosteric modulators. Neuropharmacology. 2018 Jul 1;136(Pt A):10-22. doi: 10.1016/j.neuropharm.2018.01.036. Epub 2018 Jan 31. PMID: 29407219; PMCID: PMC6027637.
  6. OCLC 919404585.{{cite book}}: CS1 maint: others (link
    )
  7. .
  8. .
  9. .
  10. ^ Evenseth LSM, Gabrielsen M, Sylte I. The GABAB Receptor-Structure, Ligand Binding and Drug Development. Molecules. 2020 Jul 7;25(13):3093. doi: 10.3390/molecules25133093. PMID: 32646032; PMCID: PMC7411975.
  11. PMID 12171574
    .
  12. .
  13. .
  14. .
  15. ^ Gidal B, Detyniecki K. Rescue therapies for seizure clusters: Pharmacology and target of treatments. Epilepsia. 2022 Sep;63 Suppl 1 (Suppl 1):S34-S44. doi: 10.1111/epi.17341. PMID: 35999174; PMCID: PMC9543841.
  16. PMID 30044221
    .
  17. .
  18. .
  19. .
  20. ^ Hanson SM, Czajkowski C. Structural mechanisms underlying benzodiazepine modulation of the GABA(A) receptor. J Neurosci. 2008 Mar 26;28(13):3490-9. doi: 10.1523/JNEUROSCI.5727-07.2008. PMID: 18367615; PMCID: PMC2410040.
  21. PMID 22446838
    .
  22. S2CID 15678338. Archived from the original
    (PDF) on 2019-03-03.
  23. .
  24. .
  25. .
  26. .
  27. .
  28. .
  29. .
  30. .
  31. .
  32. .
  33. .
  34. .
  35. .
  36. ^ Luscher B, Fuchs T, Kilpatrick CL. GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron. 2011 May 12;70(3):385-409. doi: 10.1016/j.neuron.2011.03.024. PMID: 21555068; PMCID: PMC3093971.
  37. ^ Braat S, Kooy RF. The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders. Neuron. 2015 Jun 3;86(5):1119-30. doi: 10.1016/j.neuron.2015.03.042. PMID: 26050032.
  38. S2CID 1424286
    .
  39. .
  40. .
  41. .
  42. .
  43. .
  44. ^ Macdonald RL, Kelly KM. Antiepileptic drug mechanisms of action. Epilepsia. 1995;36 Suppl 2:S2-12. doi: 10.1111/j.1528-1157.1995. tb05996.x. PMID: 8784210.
  45. ^ ten Hoeve AL (2012). GABA receptors and the immune system Archived 2013-06-13 at the Wayback Machine. Thesis, Utrecht University
  46. PMID 22319471
    .
  47. .
  48. ^ .
  49. ^ .
  50. ^ Hunter, A (2006). "Kava (Piper methysticum) back in circulation". Australian Centre for Complementary Medicine. 25 (7): 529.
  51. PMID 22787590
    .
  52. ^ Toraskar M, Singh PR, Neve S (2010). "STUDY OF GABAERGIC AGONISTS" (PDF). Deccan Journal of Pharmacology. 1 (2): 56–69. Archived from the original (PDF) on 2013-10-16. Retrieved 2013-02-12.
  53. PMID 18585399
    .
  54. .
  55. .
  56. .
  57. .
  58. .
  59. S2CID 6410599. Archived from the original
    (PDF) on 2019-02-20.
  60. ^ Weir CJ, Mitchell SJ, Lambert JJ. Role of GABAA receptor subtypes in the behavioural effects of intravenous general anaesthetics. Br J Anaesth. 2017 Dec 1;119(suppl_1):i167-i175. doi: 10.1093/bja/aex369. PMID: 29161398.
  61. PMID 17979718
    .
  62. ^ Sieghart W, Ramerstorfer J, Sarto-Jackson I, Varagic Z, Ernst M. A novel GABA(A) receptor pharmacology: drugs interacting with the α(+) β(-) interface. Br J Pharmacol. 2012 May;166(2):476-85. doi: 10.1111/j.1476-5381.2011.01779.x. PMID: 22074382; PMCID: PMC3417481.
  63. PMID 18541432
    .
  64. .
  65. .
  66. .
  67. .

Further reading

External links