GABA receptor

GABA receptor

The GABA receptors are a class of receptors that respond to the neurotransmitter γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter in the vertebrate central nervous system. There are three classes of GABA receptors: GABAA, GABAB, and GABAС.

GABAA and GABAС receptors are ligand-gated ion channels (also known as ionotropic receptors), whereas GABAB receptors are G protein-coupled receptors (also known as metabotropic receptors).

Ligand-gated ion channels


It has long been recognized that the fast response of neurons to GABA that is blocked by bicuculline and picrotoxin is due to direct activation of an anion channel.Kuffler SW, Edwards C (1958). "Mechanism of gamma-aminobutyric acid (GABA) action and its relation to synaptic inhibition". "J Neurophysiol" 21 (6): 589–610. PMID 13599049.] Kravitz EA (1963). "Gamma-aminobutyric acid and other blocking compounds in crustacea. III. Their relative concentrations in separated motor and inhibitory axons". "J Neurophysiol" 26: 739–751. PMID 14065325.] Krnjevic K, Schwartz S (1967). "The action of γ-aminobutyric acid on cortical neurones". "Expl Brain Res" 3: 320–336. PMID 6031164.] Takeuchi A, Takeuchi N (1967). "Anion permeability of the inhibitory post-synaptic membrane of the crayfish neuromuscular junction". "J Physiol" 191: 575–590. PMID 6051794. PMC|1365493.] Takeuchi A, Takeuchi N (1969). "A study of the action of picrotoxin on the inhibitory neuromuscular junction of the crayfish". "J Physiol" 205: 377–391. PMID 5357245. PMC|1348609.]

This channel was subsequently termed the GABAA receptor.Takeuchi A, Onodera K (1972). "Effect of bicuculline on the GABA receptor of the crayfish neuromuscular junction". "Nature New Biol" 236: 55–56. PMID 4502428.] Fast-responding GABA receptors are members of family of Cys-loop ligand-gated ion channels.Barnard EA "et al". (1998). "International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA Receptors: Classification on the Basis of Subunit Structure and Receptor Function". "Pharmacol Rev" 50 (2): 291–314. PMID 9647870. [ Free full text] ] Hevers W, Luddens H (1998). "The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes". "Mol Neurobiol" 18 (1): 35–86. PMID 9824848] Sieghart W, Sperk G (2002). "Subunit composition, distribution and function of GABAA receptor subtypes". "Curr Top Med Chem" 2 (8): 795–816. PMID 12171572.] Members of this superfamily, which includes nicotinic acetylcholine receptors, GABAA and GABAС receptors, glycine and 5-HT3 receptors, possess a characteristic loop formed by a disulfide bond between two cysteine residues.


A second type of ionotropic GABA receptors, insensitive to typical allosteric modulators of GABAA receptor channels such as benzodiazepines and barbiturates,Sivilotti L, Nistri A (1991). "GABA receptor mechanisms in the central nervous system". "Prog Neurobiol" 36 (1): 35–92. PMID 1847747.] Bormann J, Feigenspan A (1995). "GABAC receptors". "Trends Neurosci" 18 (2): 515–519. PMID 8638289.] Johnston, GR (1996). "GABAC receptors: relatively simple transmitter-gated ion channels?" "Trends Pharmacol Sci" 17 (9): 319–323. PMID 8885697.] was designated GABAС receptor.Drew CA, Johnston GR, Weatherby RP (1984). "Bicuculline-insensitive GABA receptors: Studies on the binding of (β)-baclofen to rat cerebellar membranes". "Neurosci Lett" 52 (3): 317–321. PMID 6097844.] Zhang D, Pan ZH, Awobuluyi M, Lipton SA (2001). "Structure and function of GABAC receptors: a comparison of native versus recombinant receptors". "Trends Pharmacol Sci" 22 (3): 121–132. PMID 11239575.]

Native responses of the GABAС receptor type occur in retinal bipolar or horizontal cells across vertebrate species.Feigenspan A, Wassle H, Bormann J (1993). "Pharmacology of the GABA receptor C1─ channel in rat retina bipolar cells". "Nature" 361 (6408): 159–162. PMID 7678450.] Quian H, Dowling JE (1993). "Novel GABA responses from rod-driven retinal horizontal cells". "Nature" 361 (6408): 162–164. PMID 8421521.] Lukasiewicz PD (1996). "GABAC receptors in the vertebrate retina". "Mol Neurobiol" 12 (3): 181–194. PMID 8884747.] Wegelius K "et al". (1998). "Distribution of GABA receptor rho subunit transcripts in the rat brain". "Eur J Neurosci" 10 (1): 350–357. PMID 9753143.] GABAС receptors are exclusively composed of ρ subunits that are related to GABAA receptor subunits.Shimada S, Cutting GR, Uhl GR (1992). "γ-Aminobutyric acid A or C receptor? γ-aminobutyric acid ρ1 receptor RNA induces bicuculline-, barbiturate-, and benzodiazepine-insensitive γ-aminobutyric acid responses in Xenopus oocytes". "Mol Pharmacol" 41 (4): 683–687. PMID 1314944.] Kusama T "et al". (1993). "Pharmacology of GABAρ1 and GABAα/β receptors expressed in Xenopus oocytes and Cos cells". "Br J Pharmacol" 109 (1): 200–206. PMID 8388298.] Kusama T, Wang TL, Guggino WB, Cutting GR, Uhl GR (1993). "GABA rho2 receptor pharmacological profile: GABA recognition site similarities to rho1". "Eur J Pharmacol" 245 (1): 83–84. PMID 8386671.]

Although the term "GABAС receptor" is frequently used, GABAС may be viewed as a variant within the GABAA receptor family. However others have argued that the differences between GABAС and GABAA receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors.Chebib M, Johnston GA (2000). "GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology.". "J Med Chem" 43 (8): 1427-47. PMID 10780899.]

Common characteristics

In ionotropic GABAA and GABAС receptors, binding of GABA molecules to their binding sites in the extracellular part of receptor triggers opening of a chloride ion-selective pore. The increased chloride conductance drives the membrane potential towards the reversal potential of the Cl¯ ion which is about –80 mV in neurons, inhibiting the firing of new action potentials.

However, there are numerous reports of excitatory GABAA receptors. This phenomenon is due to increased intracellular concentration of Cl¯ ions either during development of the nervous systemcite journal |author=Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa JL |title=GABAA, NMDA and AMPA receptors: a developmentally regulated 'ménage à trois' |journal=Trends Neurosci. |volume=20 |issue=11 |pages=523–9 |year=1997 |month=November |pmid=9364667 |doi= |url=] cite journal |author=Taketo M, Yoshioka T |title=Developmental change of GABA(A) receptor-mediated current in rat hippocampus |journal=Neuroscience |volume=96 |issue=3 |pages=507–14 |year=2000 |pmid=10717431 |doi= |url=] or in certain cell populations.cite journal |author=Tomiko SA, Taraskevich PS, Douglas WW |title=GABA acts directly on cells of pituitary pars intermedia to alter hormone output |journal=Nature |volume=301 |issue=5902 |pages=706–7 |year=1983 |month=February |pmid=6828152 |doi= |url=] cite journal |author=Cherubini E, Gaiarsa JL, Ben-Ari Y |title=GABA: an excitatory transmitter in early postnatal life |journal=Trends Neurosci. |volume=14 |issue=12 |pages=515–9 |year=1991 |month=December |pmid=1726341 |doi= |url=] cite journal |author=Lamsa K, Taira T |title=Use-dependent shift from inhibitory to excitatory GABAA receptor action in SP-O interneurons in the rat hippocampal CA3 area |journal=J. Neurophysiol. |volume=90 |issue=3 |pages=1983–95 |year=2003 |month=September |pmid=12750426 |doi=10.1152/jn.00060.2003 |url=]

After this period of development, a Chloride pump is upregulated and inserted into the cell membrane, pumping Cl- ions into the extracellular space of the cell. Further openings via GABA binding to the receptor then produce inhibitory responses. Over-excitation of this receptor induces receptor remodeling and the eventual invagination of the GABA receptor. As a result, further GABA binding becomes inhibited and IPSPs are no longer relevant.

G protein coupled receptor: GABAB

A slow response to GABA is mediated by GABAB receptors,Bowery NG "et al". (2002). "International Union of Pharmacology. XXXIII. Mammalian γ-Aminobutyric AcidB Receptors: Structure and Function". "Pharmacol Rev" 54 (2): 247–264. PMID 12037141. [ Free full text] ] originally defined on the basis of pharmacological properties.Bowery NG "et al". (1980). "(β)-Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor". "Nature" 283 (5742): 92–94. PMID 6243177.]

In studies focused on the control of neurotransmitter release, it was noted that a GABA receptor was responsible for modulating evoked release in a variety of isolated tissue preparations. This ability of GABA to inhibit neurotransmitter release from these preparations was not blocked by bicuculline, was not mimicked by isoguvacine, and was not dependent on Cl¯, all of which are characteristic of the GABAA receptor. The most striking discovery was the finding that baclofen (β-parachlorophenyl GABA), a clinically employed spasmolyticBein HJ (1972). "Pharmacological differentiations of muscle relaxants". In: Birkmayer W (ed.) "Spasticity: A Topical Survey", pp. 76–89. Vienna: Hans Huber. ] Keberle H, and Faigle JW (1972) "Synthesis and structure-activity relationship of the gamma-aminobutyric acid derivatives". In: Birkmayer W (ed.) "Spasticity: A Topical Survey", pp. 76–89. Vienna: Hans Huber. ] mimicked, in a stereoselective manner, the effect of GABA.

Later ligand-binding studies provided direct evidence of binding sites for baclofen on central neuronal membranes.Hill DR, Bowery NG (1981). " [3H] -baclofen and [3H] -GABA bind to bicuculline insensitive GABAB sites in rat brain". "Nature" 290 (5802): 149–152. PMID 6259535.] cDNA cloning confirmed that the GABAB receptor belongs to the family of G-protein coupled receptors.Kaupmann K "et al". (1997). "Expression cloning of GABAB receptors uncovers similarity to metabotropic glutamate receptors". "Nature" 386 (6622): 239–246. PMID 9069281.] Additional information on GABAB receptors has been reviewed elsewhere.Enna SJ (1997). "GABAB receptor agonists and antagonists: pharmacological properties and therapeutic possibilities". "Expert Opin Investig Drugs" 6 (10): 1319–1325. PMID 15989503.] Enna SJ, Bowery NG (1997). In: "The GABA Receptors", 2nd ed. Totowa, NJ: Humana Press. ] Kaupmann K "et al". (1998). "GABAB-receptor subtypes assemble into functional heteromeric complexes". "Nature" 396 (6712): 683–687. PMID 9872317.] Kaupmann K "et al". (1998). "Human gamma-aminobutyric acid type B receptors are differentially expressed and regulate inwardly rectifying K+ channels". "Proc Natl Acad Sci USA" 95 (25): 14991–14996. PMID 9844003. PMC|24563.] Marshall FH, Jones KA, Kaupmann K, Bettler B (1999). "GABAB receptors−the first 7TM heterodimers". "Trends Pharmacol Sci" 20 (10): 396–399. PMID 10498952.] Marshall FH, White J, Main M, Green A, Wise A (1999). "GABAB receptors function as heterodimers". "Biochem Soc Trans" 27 (4): 530–535. PMID 10917635.] Bowery NG, Enna SJ (2000). "gamma-aminobutyric acid(B) receptors: first of the functional metabotropic heterodimers". "J Pharmacol Exp Ther" 292 (1): 2–7. PMID 10604925. Erratum in "J Pharmacol Exp Ther" 293 (1): 313.] Enna SJ (2000). "GABAB receptor signaling pathways". In: Mohler H (ed.) "Pharmacology of GABA and Glycine Neurotransmission", pp. 329–342. Berlin: Springer-Verlag. ISBN 3540676163]


Thus, GABAA and GABAС receptors are ligand-gated ion channels, whereas GABAB receptors are G protein-coupled receptors.

This has a parallel to several other systems in the body, where a single molecule binds to receptors which function in completely different ways:

* acetylcholine binds to nicotinic and muscarinic receptors
* serotonin binds to 5-HT3 and metabotropic receptors
* glutamate binds to ionotropic and metabotropic receptors
* purines bind to ionotropic nucleotide-gated P2X and G protein-coupled P2Y receptors


External links

* [ IUPHAR GPCR Database - GABAB receptors]

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