GABAC Receptors

The term GABA_C receptor was first proposed by Johnston and coworkers in 1986 to describe a bicuculline- and baclofen-insensitive [³H]-GABA binding site present on cerebellar membranes. Subsequent work has shown that GABA_C receptors are ligand-gated chloride channels that are present in many parts of the brain including the superior colliculus, cerebellum, hippocampus, and, most prominently, the retina. Our current knowledge of GABA_C receptors comes mainly from studies performed in the visual system, particularly on retinal neurons. GABA_C receptors are highly sensitive to GABA, which displays an EC₅₀ value of ~1 µM. Activation of GABA_C receptors gives rise to sustained responses with slow onset and offset kinetics. The time constants of GABA_C receptor relaxation are in the order of tens of seconds, which makes them the slowest ligand-gated channels identified to date. The chloride channels gated by GABA_C receptors exhibit small single channel conductances (a few picosiemens). 

GABA_C receptors are thought to be composed of GABA ρ (rho) subunits. At least three types of GABA ρ subunits have now been cloned from retinal cDNA libraries: human ρ1 and its shorter alternative spliced forms (D51 and D450); human ρ2; and rat ρ1-3. Although most of the GABA ρ subunits could readily form functional homo-oligomeric receptors when expressed in Xenopus oocyte or mammalian cell lines, it is believed that the neuronal GABA_C receptors are most likely formed by hetero-oligomeric GABA ρ subunits. In addition, recent studies have suggested that some GABA ρ subunits could co-assemble with GABA_A receptor γ2 subunit to form the hetero-oligomeric receptors with distinct properties. Thus, the molecular compositions of the native GABA_C receptors are likely more complicated than original thought.

In terms of their pharmacology, GABA_C receptors are not blocked by traditional GABA_A receptor antagonists, such as bicuculline and SR-95531. Furthermore, they are not modulated by a range of GABA_A receptor ligands, including benzodiazepines, barbiturates and some neurosteroids. GABA_C receptors are also insensitive to baclofen, a highly selective GABA_B receptor agonist, and likewise neither phaclofen nor saclofen, two GABA_B receptor antagonists, block GABA_C responses. In contrast, picrotoxin, a chloride channel blocker, has been shown to antagonize GABA_C receptors. On rat retinal neurons, however, GABA_C receptors are insensitive to picrotoxin due to a mutation in the GABA ρ2 subunit.

The first selective GABA_C receptor agonist to be described was cis-4-aminocrotonic acid (CACA), although some studies indicate that it may also act on other GABA receptors and GABA transporters. In contrast, certain GABA_A and GABA_B receptor agonists act as antagonists at GABA_C receptors. Among them, imidazole-4-acetic acid (I4AA), a partial agonist at the GABA_A receptor, has been shown to inhibit GABA_C receptors on retinal neurons. Furthermore, recent studies have indicated that I4AA can also partially activate certain subtypes of GABA_C receptor. Therefore, I4AA might be useful to distinguish various forms of GABA_C receptors. On the other hand, 3-aminopropyl(methyl)phosphonic acid (APMPA), a GABA_B receptor agonist, acts as a potent antagonist on the GABA_C receptors. Finally, 1,2,5,6-tetrahydropyridine-4-yl-methylphosphinic acid (TPMPA) has been described as a selective GABA_C receptor antagonist. Because it is a low affinity, competitive antagonist at GABA_C receptors, high concentrations of TPMPA should be used to completely block GABA responses.

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

Currently Accepted Name	GABAC
Structural Information	GABA ρ1 subunit 473 aa (human) GABA ρ2 subunit 465 aa (human) GABA ρ3 subunit 464 aa (rat)
Agonist	GABA (A2129)
Partial Agonists	Isoguvacine (G002) Muscimol (M1523) Muscimol hydrobromide (G019) CACA
Antagonists	TPMPA (T200) 3-APMPA I4AAa (219991) Picrotoxin (P1675)
Partial Antagonists	THIP (Gaboxadol) (T101) P4S (P9159)
Modulators	Zn2+ La3+
Signal Transduction Mechanism	Cl– influx
Radioligand of Choice	[3H]-Muscimol
Tissue Expression	Retina, superior colliculus, hippocampus, cerebellum, lateral geniculate nucleus, amygdala
Physiological Function	Neuronal inhibition
Disease Relevance	Not Known

Footnotes

a) I4AA is a partial agonist on some GABA_C receptors.

Abbreviations

3-APMPA: 3-Aminopropyl-(methyl)phosphinic acid
CACA: cis-4-Aminocrotonic acid
I4AA: Imidazol-4-acetic acid
P4S: Piperidine-4-sulphonic acid
THIP: 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol
TPMPA: (1,2,5,6-tetrahydropyridine-4-yl)-methylphosphinic acid

References

1. Bormann J. 2000. The ?ABC? of GABA receptors. Trends in Pharmacological Sciences. 21(1):16-19. https://doi.org/10.1016/s0165-6147(99)01413-3

2. Chebib M, Vandenberg RJ, Froestl W, Johnston GA. 1997. Unsaturated phosphinic analogues of ?-aminobutyric acid as GABAC receptor antagonists. European Journal of Pharmacology. 329(2-3):223-229. https://doi.org/10.1016/s0014-2999(97)89183-2

3. Johnston G, Chebib M, Hanrahan J, Mewett K. 2003. GABAC Receptors as Drug Targets. CDTCNSND. 2(4):260-268. https://doi.org/10.2174/1568007033482805

4. Craig Venter J, Richard W, Olsen. 1986. Benzodiazepine/GABA Receptors and Chloride Channels. New York: A.R. Liss.

5. Johnston GAR, Chebib M, Hanrahan JR, Mewett KN. 2010. Neurochemicals for the Investigation of GABAC Receptors. Neurochem Res. 35(12):1970-1977. https://doi.org/10.1007/s11064-010-0271-7

6. Martinez-Torres A, Vazquez AE, Panicker MM, Miledi R. 1998. Cloning and functional expression of alternative spliced variants of the  1  -aminobutyrate receptor. Proceedings of the National Academy of Sciences. 95(7):4019-4022. https://doi.org/10.1073/pnas.95.7.4019

7. Milligan CJ. 2004. Evidence for Inhibition Mediated by Coassembly of GABAA and GABAC Receptor Subunits in Native Central Neurons. Journal of Neuroscience. 24(33):7241-7250. https://doi.org/10.1523/jneurosci.1979-04.2004

8. Ng CK, Kim H, Gavande N, Yamamoto I, Kumar RJ, Mewett KN, Johnston GA, Hanrahan JR, Chebib M. 2011. Medicinal chemistry of ? GABACreceptors. Future Medicinal Chemistry. 3(2):197-209. https://doi.org/10.4155/fmc.10.286

9. Perfilova V, Tiurenkov I. 2011. GABAC receptors: structure and functions. Eksperimental'naia i klinicheskaia farmakologiia. 74(1):45.

10. Qian H, Ripps H. 1999. Response kinetics and pharmacological properties of heteromeric receptors formed by coassembly of GABA rho- and gamma2-subunits. Proc. R. Soc. Lond. B. 266(1436):2419-2425. https://doi.org/10.1098/rspb.1999.0941

11. Qian H, Ripps H. 2001. Chapter 20 The GABAC receptors of retinal neurons.295-308. https://doi.org/10.1016/s0079-6123(01)31024-5

12. Qian H, Dowling J, Ripps H. 1998. Molecular and pharmacological properties of GABA‐ρ subunits from white perch retina. Journal of Neurobiology.. 37(2):305-20.

13. Ragozzino D, Woodward R, Murata Y, Eusebi F, Overman L, Miledi R. 1996. Design and in vitro pharmacology of a selective gamma-aminobutyric acidC receptor antagonist. Molecular Pharmacology. 50(4):1024-30.

14. Tiedje K, Stevens K, Barnes S, Weaver D. 2010. ?-Alanine as a small molecule neurotransmitter. Neurochemistry International. 57(3):177-188. https://doi.org/10.1016/j.neuint.2010.06.001

15. Woodward R, Polenzani L, Miledi R. 1992. Characterization of bicuculline/baclofen-insensitive gamma-aminobutyric acid receptors expressed in Xenopus oocytes. I. Effects of Cl-channel inhibitors.. Molecular pharmacology. 42(1):165-73.

16. Zhang D, Pan Z, Awobuluyi M, Lipton SA. 2001. Structure and function of GABAC receptors: a comparison of native versus recombinant receptors. Trends in Pharmacological Sciences. 22(3):121-132. https://doi.org/10.1016/s0165-6147(00)01625-4