GABA receptor

from Wikipedia, the free encyclopedia

GABA receptors are transmembrane proteins in nerve cells that specifically bind the neurotransmitter γ-aminobutyric acid (GABA - abbreviation for gamma-aminobutyric acid). There are two main groups of GABA receptors: ion channel receptors ( ionotropic receptors) and secondary signaling ( metabotropic ) receptors. The ionotropic receptors include the GABA A and GABA A ρ receptors, and the metabotropic ones the GABA B receptor.

GABA A receptors

GABA A receptor with binding sites for various substances.

construction

GABA A receptors are ligand- activated ion channels that are permeable to chloride and hydrogen carbonate ions. They are heteropentamers, that is, they are made up of five different subunits (from the Greek penta- , “five”, hétero , “different” and méros , “part”). Each subunit spans the cell membrane four times. There are eight classes of homologous subunits.

  • α (with 6 representatives; α 1 –α 6 )
  • β (with 3 representatives; β 1 –β 3 )
  • γ (with 3 representatives; γ 1 –γ 3 )
  • δ, ε, π, θ (each with one representative)
  • ρ (with 3 representatives; ρ 1 –ρ 3 )

Most of the GABA A receptors in the brain are made up of two α, two β and one γ subunits. In addition to the binding site for γ-aminobutyric acid , the functional GABA A receptor has additional, allosteric binding sites for benzodiazepines on the γ subunit and for barbiturates and neurosteroids on the β subunit. Receptors that are composed exclusively of ρ subunits are referred to as GABA A -ρ receptors .

function

The GABA A receptor is very widespread in the brain and spinal cord and is the most important inhibitory receptor in the central nervous system (CNS). It gets its effect by increasing the permeability for Cl ions, which triggers an IPSP . GABA accounts for 30% of the amount of transmitters in the CNS. It has a special function in the basal ganglia and the cerebellum , where it is involved in motor control. The Purkinje cell of the cerebellum is z. B. GABAerg. In the thalamus, GABA works to induce and maintain sleep . This is also the main target for pharmacological influences from benzodiazepines and barbiturates (see above). In the spinal cord there are GABA receptors on motor neurons , and they are involved in the reflex circuit as well as the coordination of movement sequences (see: Renshaw cells ). Some functional differences are related to the different α-subunits:

  • α 1 subunits occur in receptors that mediate the sedative effect of benzodiazepines ( diazepam ).
  • α 2 subunits are associated with the anxiolytic (anxiety-relieving) function of the receptor, and
  • α 3 subunits occur in receptors that primarily have a muscle-relaxing effect.

Influenced by alcohol

  • Alcohol binds to the GABA A receptor and leads to hyperpolarization by increasing the permeability for chloride ions on the nerve cell membrane, whereby the action potential frequency decreases. Since at the same time the most important excitatory system is inhibited by influencing the NMDA receptor , there is an overall sedative effect.

Pharmacological influence

  • Tranquilizers such as benzodiazepines increase the sedative , anxiolytic and anticonvulsant effects of GABA.
  • Barbiturates are able to activate the GABA A receptor without GABA and, along with other sedatives , can be used in anesthesia to induce anesthesia .
  • Muscimol is the active ingredient of the toadstool and an agonist of the GABA A receptor and is responsible for its hallucinogenic effect.
  • Bicuculline is an antagonist of the GABA A receptor. This active ingredient has only experimental, but no clinical relevance.
  • α- Thujone is possibly a non-competitive antagonist at the GABA A receptor. This may be the reason for its convulsive effect.
  • Picrotoxin blocks the chloride channel of the GABA A receptor.
  • Antiepileptic drugs such as valproate also inhibit the breakdown of GABA and are prescribed to prevent epileptic seizures from occurring.
  • Tiagabine is a selective GABA reuptake inhibitor and is also said to increase the concentration of GABA in the synaptic cleft to prevent epilepsy from occurring.
  • Neurosteroids are breakdown products of androgens and progesterones . They occur physiologically in the body and have a modulating effect on GABA A receptors.
  • Alphaxalone is a synthetically produced neurosteroid and is used in analgesia .
  • Diazepam-binding inhibitor (DBI) binds to the benzodiazepine binding site and thereby displaces benzodiazepines from it. The presence of DBI in the nervous system shows that there are also physiological agonists of the benzodiazepine binding site. The function of this peptide is still unclear.
  • Some β-carboline -3-carboxamides act as negative allosteric modulators at the benzodiazepine binding site , which means that they favor the closed conformation of the ion channel. The derivative FG-7142 causes anxiety. However, this effect is mediated , at least in part, by the 5-HT 2C receptor . Its activation causes GABA-ergic stimulation.
  • Flumazenil , a competitive antagonist at the benzodiazepine binding site, serves as an antidote for benzodiazepine sedatives.
  • The general anesthetics etomidate and propofol work almost exclusively via GABA A receptors. They mediate the immobilizing effect (no reaction to painful stimuli such as e.g. during surgery) via GABA A receptors in the spinal cord, which are probably composed of α 3 and α 5 , β 3 and γ 2 subunits . The hypnotic (sleep-inducing) effect is mediated , among other things, by GABA A receptors containing α 5 , β 3 and γ 2 . The exact location of these receptors and other subunits that mediate hypnosis are still unknown. The sedative (no response to verbal stimuli / commands) effects of etomidate and propofol are likely mediated by GABA A receptors containing α 1 , β 2 and γ 2 in the neocortex .
  • 4-Hydroxybutanoic acid (GHB) addresses α4βδ GABA A receptors.

A considerable number of substances that have a stimulating effect on the GABA A receptor are addictive . This is especially true for the large substance classes of barbiturates and benzodiazepines. The addiction is mediated via α 1 -containing receptors on interneurons in the ventral tegmentum . Their stimulation causes the functional change of AMPA receptors , which are located on this neuron , in a neuroplastic process .

GABA receptors are subject to pharmacological tolerance . This means that when drugs that affect the receptor are given, an ever larger dose is required over time to achieve the same effect.

Triggers paradoxical reactions

A large number of substances that normally act as agonists on the GABA A receptor can become antagonists due to a deviation in the composition of the five subunits of the receptor (see figure). You achieve the opposite effect, which is called the paradoxical reaction . Alcohol, for example, does not have a calming or relaxing effect, but creates nervousness and inner restlessness.

It is assumed that genetic and epigenetic deviations underlie the corresponding changes in the GABA A receptors. The latter are seen as a possible reason that such a structural reorganization of the receptors only occurs in the course of life, triggered for example by special stress.

The paradoxical reactions have an often underestimated importance in the field of anesthesiology , the treatment of epilepsy and in psychiatry . If the possibility of a paradoxical reaction is known for a substance used here, it is recommended to monitor the course of treatment specifically for this and to have pharmaceutical antidotes ( antidotes ) ready.

GABA A rho receptors

GABA A -ρ receptors, formerly known as GABA C -receptors , are not inhibited by bicuculline and are almost insensitive to benzodiazepines, barbiturates and neurosteroids. They activate and inactivate more slowly than the GABA A receptors and hardly desensitize.

GABA A -ρ receptors are mainly found in the retina and, to a lesser extent , in the hippocampus , the superior colliculi and the spinal cord .

GABA A ρ receptors have the same structure as GABA A receptors and are therefore not proposed as an independent GABA receptor subtype by the International Union of Pharmacology . The differences between GABA A -ρ receptors and GABA A -receptors are their pharmacology (see above), their composition (GABA A -ρ-receptors are made up exclusively of ρ-subunits, the typical GABA A -receptor consists of α-, β and γ subunits) and the time constants of their activation and deactivation. There are three subunits ρ 1 –ρ 3 .

GABA B receptors

The metabotropic GABA B receptor is a G protein-coupled receptor , and is from a transmembrane protein with seven transmembrane domains formed. The signal transduction is mediated by a G i protein and leads postsynaptically to an activation of ligand-controlled potassium channels and thus to an IPSP and, presynaptically, in addition to the potassium channel activation, also to a closure of voltage-controlled calcium channels . GABA B receptors are often also located in the presynaptic membrane. Here, the decrease in calcium concentration leads to a reduced release of transmitters from the presynapse. The agonist at the GABA B receptor is baclofen . Functional GABA B receptors are formed by the heteromeric connection of GABA B 1 with GABA B 2 subunits, which together form a heterodimer. The carboxy terminus of GABA B 2 is in turn connected intracellularly with two tetramers each of the so-called KCTD proteins ("KCTD" for potassium channel tetramerization domain-containing ). The KCTD proteins enhance the response to agonists, accelerate G protein activation and desensitization.

further reading

swell

  1. ↑ Susanne Rösner: Meta-analysis on the effectiveness of acamprosate and naltrexone in the treatment of withdrawal from alcohol-dependent patients. (PDF) 2006, accessed December 15, 2014 .
  2. ↑ KM Höld ​​et al .: Alpha-thujone (the active component of absinthe): gamma-aminobutyric acid type A receptor modulation and metabolic detoxification . In: Proc. Natl. Acad. Sci. USA Volume 97, 2000, pp. 3826-3831. PMID 10725394 HTML
  3. ↑ J. Auta, PJ Winsauer, WB Faust, P. Lambert, JM Moerschbaecher: Effects of negative allosteric modulators of gamma-aminobutyric acid A receptors on complex behavioral processes in monkeys . In: J Pharmacol Exp Ther . tape 280 , no. 1 , 1997, p. 316-325 , PMID 8996212 .
  4. ↑ EA Hackler, GH Turner, PJ Gresch et al: 5-Hydroxytryptamine2C receptor contribution to m-chlorophenylpiperazine and N-methyl-beta-carboline-3-carboxamide-induced anxiety-like behavior and limbic brain activation . In: J. Pharmacol. Exp. Ther. tape 320 , no. 3 , 2007, p. 1023-1029 , doi : 10.1124 / jpet.106.113357 , PMID 17138863 .
  5. ↑ RW Invernizzi, M. Pierucci, E. Calcagno et al .: Selective activation of 5-HT (2C) receptors stimulates GABA-ergic function in the rat substantia nigra pars reticulata: a combined in vivo electrophysiological and neurochemical study . In: Neuroscience . tape 144 , no. 4 , 2007, p. 1523-1535 , doi : 10.1016 / j.neuroscience.2006.11.004 , PMID 17161544 .
  6. ↑ Klaus Aktories, Ulrich Förstermann, Franz Hofmann, Klaus Starke: General and special pharmacology and toxicology . 10th edition. Elsevier, Urban & Fischer, Munich / Jena 2009, ISBN 978-3-437-42522-6 .
  7. ↑ U. Rudolph, B. Antkowiak: Molecular and neuronal substrates for general anesthetics . In: Nat Rev Neurosci . Volume 5, 2004, pp. 709-720. PMID 15322529
  8. ↑ N. Absalom et al .: α4βδ GABAA receptors are high-affinity targets for γ-hydroxybutyric acid (GHB). In: Proc Natl Acad Sci . Volume 109, 2012, p. 13404. PMID 22753476
  9. ↑ C. Bocklisch, K. Tan, C. Lüscher: Why sleeping pills like Valium are addicting. In: Spectrum of Science . 2010. Article page
  10. ↑ C. Robin, N. Trieger: Paradoxical reactions to benzodiazepines in intravenous sedation: a report of 2 cases and review of the literature. In: Anesthesia progress. Volume 49, Number 4, 2002, pp. 128-132, PMID 12779114 , PMC 2007411 (free full text) (review).
  11. ↑ Carol Paton: Benzodiazepines and disinhibition: a review. In: Psychiatric Bulletin. 26, 2002, p. 460, doi : 10.1192 / pb.26.12.460 , PDF .
  12. ↑ T. Bäckström, M. Bixo, M. Johansson, S. Nyberg, L. Ossewaarde, G. Ragagnin, I. Savic, J. Strömberg, E. Timby, F. van Broekhoven, G. van Wingen: Allopregnanolone and mood disorders. In: Progress in neurobiology. Volume 113, February 2014, pp. 88-94, doi : 10.1016 / j.pneurobio.2013.07.005 , PMID 23978486 (review), PDF .
  13. ^ EN Brown, R. Lydic, ND Schiff: General anesthesia, sleep, and coma. In: The New England Journal of Medicine . Volume 363, number 27, December 2010, pp. 2638-2650, doi : 10.1056 / NEJMra0808281 , PMID 21190458 , PMC 3162622 (free full text) (review).
  14. ^ EA Barnard et al: International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acid A receptors: classification on the basis of subunit structure and receptor function . In: Pharmacol Rev . Volume 50, 1998, pp. 291-313. PMID 9647870 HTML
  15. ↑ K. Aktories: Pharmacology and Toxicology. 9th edition.
  16. ↑ J. Schwenk, M. Metz, G. Zolles et al: Native GABA (B) receptors are heteromultimers with a family of auxiliary subunits . In: Nature . tape 465 , no. 7295 , 2010, p. 231-235 , doi : 10.1038 / nature08964 , PMID 20400944 .

Web links