GABAA receptor
The GABAA receptor (GABAAR) is an
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
The
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
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
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
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
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
In humans, the units are as follows:
- six types of α subunits ()
- three βs (GABRB1, GABRB2, GABRB3)
- three γs (GABRG2, GABRG3)
- as well as a δ (GABRD), an ε (GABRE), a π (GABRP), and a θ (GABRQ)
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.
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
A number of
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
- Orthosteric agonists: (partial agonist).
- Orthosteric antagonists: bicuculline, gabazine.
- Positive allosteric modulators:
- Negative allosteric modulators: flumazenil, Ro15-4513, sarmazenil, pregnenolone sulfate, amentoflavone, and zinc.[57]
- Inverse allosteric agonists: ).
- Second-order modulators: (−)‐epigallocatechin‐3‐gallate.[58]
- Non-competitive channel blockers: cicutoxin, oenanthotoxin, pentylenetetrazol, picrotoxin[citation needed], thujone, and lindane.
Effects
Ligands which contribute to receptor activation typically have
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]
- CL-218,872 (highly α1-selective agonist)
- bretazenil (subtype-selective partial agonist)
- imidazenil and L-838,417 (both partial agonists at some subtypes, but weak antagonists at others)
- QH-ii-066 (full agonist highly selective for α5 subtype)
- α5IA (selective inverse agonist for α5 subtype)
- α1 and α5
- 3-acyl-4-quinolones: selective for α1 over α3[63]
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
- ^ 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.
- )
- S2CID 4330077.
- ^ 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.
- ^ 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.
- )
- S2CID 41704867.
- PMID 17591544.
- PMID 8783370.
- ^ 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.
- PMID 12171574.
- PMID 15530567.
- S2CID 83817337.
- PMID 9647870.
- ^ 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.
- PMID 30044221.
- PMID 12871032.
- PMID 18367615.
- S2CID 72023197.
- ^ 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.
- PMID 22446838.
- S2CID 15678338. Archived from the original(PDF) on 2019-03-03.
- PMID 23116339.
- PMID 17544304.
- PMID 24909990.
- PMID 30044221.
- PMID 29950725.
- PMID 14627650.
- S2CID 18552767.
- PMID 32633279.
- PMID 2575165.
- PMID 20194137.
- ISBN 978-0-397-51820-3.
- S2CID 6433030.
- PMID 9691220.
- ^ 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.
- ^ 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.
- S2CID 1424286.
- S2CID 14457042.
- PMID 18760291.
- PMID 33683511.
- PMID 8550630.
- S2CID 26123520.
- ^ 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.
- ^ ten Hoeve AL (2012). GABA receptors and the immune system Archived 2013-06-13 at the Wayback Machine. Thesis, Utrecht University
- PMID 22319471.
- PMID 12223227.
- ^ PMID 11850512.
- ^ PMID 2464409.
- ^ Hunter, A (2006). "Kava (Piper methysticum) back in circulation". Australian Centre for Complementary Medicine. 25 (7): 529.
- PMID 22787590.
- ^ 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.
- PMID 18585399.
- S2CID 13179025.
- S2CID 24194421.
- PMID 24460753.
- S2CID 24096465.
- PMID 15451406.
- S2CID 6410599. Archived from the original(PDF) on 2019-02-20.
- ^ 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.
- PMID 17979718.
- ^ 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.
- PMID 18541432.
- PMID 12779114.
- ISSN 0955-6036.
- S2CID 207407084.
- PMID 21190458.
Further reading
- Olsen RW, DeLorey TM (1999). "Chapter 16: GABA and Glycine". In Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD (eds.). Basic neurochemistry: molecular, cellular, and medical aspects (Sixth ed.). Philadelphia: Lippincott-Raven. ISBN 978-0-397-51820-3.
- Olsen RW, Betz H (2005). "Chapter 16: GABA and Glycine". In Siegel GJ, Albers RW, Brady S, Price DD (eds.). Basic Neurochemistry: Molecular, Cellular and Medical Aspects (Seventh ed.). Boston: Academic Press. pp. 291–302. ISBN 978-0-12-088397-4.
- Uusi-Oukari M, Korpi ER (March 2010). "Regulation of GABA(A) receptor subunit expression by pharmacological agents" (PDF). Pharmacological Reviews. 62 (1): 97–135. S2CID 12202117. Archived from the original(PDF) on 2020-02-28.
- Rudolph U (2015). Diversity and Functions of GABA Receptors: A Tribute to Hanns Möhler (First ed.). Academic Press, Elsevier. ISBN 978-0-12-802660-1.
External links
- Receptors,+GABA-A at the U.S. National Library of Medicine Medical Subject Headings (MeSH)