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.

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