The term GABAC 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 GABAC 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 GABAC receptors comes mainly from studies performed in the visual system, particularly on retinal neurons. GABAC receptors are highly sensitive to GABA, which displays an EC50 value of ~1 µM. Activation of GABAC receptors gives rise to sustained responses with slow onset and offset kinetics. The time constants of GABAC 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 GABAC receptors exhibit small single channel conductances (a few picosiemens).
GABAC 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 GABAC 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 GABAA receptor γ2 subunit to form the hetero-oligomeric receptors with distinct properties. Thus, the molecular compositions of the native GABAC receptors are likely more complicated than original thought.
In terms of their pharmacology, GABAC receptors are not blocked by traditional GABAA receptor antagonists, such as bicuculline and SR-95531. Furthermore, they are not modulated by a range of GABAA receptor ligands, including benzodiazepines, barbiturates and some neurosteroids. GABAC receptors are also insensitive to baclofen, a highly selective GABAB receptor agonist, and likewise neither phaclofen nor saclofen, two GABAB receptor antagonists, block GABAC responses. In contrast, picrotoxin, a chloride channel blocker, has been shown to antagonize GABAC receptors. On rat retinal neurons, however, GABAC receptors are insensitive to picrotoxin due to a mutation in the GABA ρ2 subunit.
The first selective GABAC 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 GABAA and GABAB receptor agonists act as antagonists at GABAC receptors. Among them, imidazole-4-acetic acid (I4AA), a partial agonist at the GABAA receptor, has been shown to inhibit GABAC receptors on retinal neurons. Furthermore, recent studies have indicated that I4AA can also partially activate certain subtypes of GABAC receptor. Therefore, I4AA might be useful to distinguish various forms of GABAC receptors. On the other hand, 3-aminopropyl(methyl)phosphonic acid (APMPA), a GABAB receptor agonist, acts as a potent antagonist on the GABAC receptors. Finally, 1,2,5,6-tetrahydropyridine-4-yl-methylphosphinic acid (TPMPA) has been described as a selective GABAC receptor antagonist. Because it is a low affinity, competitive antagonist at GABAC 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.
a) I4AA is a partial agonist on some GABAC receptors.
3-APMPA: 3-Aminopropyl-(methyl)phosphinic acid
CACA: cis-4-Aminocrotonic acid
I4AA: Imidazol-4-acetic acid
P4S: Piperidine-4-sulphonic acid
TPMPA: (1,2,5,6-tetrahydropyridine-4-yl)-methylphosphinic acid
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