A second type of ionotropic GABA receptor, insensitive to typical allosteric modulators of GABA_A receptor channels such as benzodiazepines and barbiturates,^[2][3][4] was designated GABA_С receptor.^[5][6] Native responses of the GABA_C receptor type occur in retinal bipolar or horizontal cells across vertebrate species.^{[7][8][9][10]}

GABA_С receptors are exclusively composed of ρ (rho) subunits that are related to GABA_A receptor subunits.^[11][12][13] Although the term “GABA_С receptor” is frequently used, GABA_С may be viewed as a variant within the GABA_A receptor family.^[14] Others have argued that the differences between GABA_С and GABA_A receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors.^[15][16] However, since GABA_С receptors are closely related in sequence, structure, and function to GABA_A receptors and since other GABA_A receptors besides those containing ρ subunits appear to exhibit GABA_С pharmacology, the Nomenclature Committee of the IUPHAR has recommended that the GABA_С term no longer be used and these ρ receptors should be designated as the ρ subfamily of the GABA_A receptors (GABA_A-ρ).^[17]

In addition to containing a GABA binding site, the GABA_A-ρ receptor complex conducts chloride ions across neuronal membranes. Binding of GABA to the receptor results in opening of this channel. When the reversal potential of chloride is less than the membrane potential, chloride ions flow down their electrochemical gradient into the cell. This influx of chloride ions lowers the membrane potential of the neuron, thus hyperpolarizes it, making it more difficult for these cells to conduct electrical impulses in the form of an action potential. Following stimulation by GABA, the chloride current produced by GABA_A-ρ receptors is slow to initiate but sustained in duration. In contrast, the GABA_A receptor current has a rapid onset and short duration. GABA is about 10 times more potent at GABA_A-ρ than it is at most GABA_A receptors.

Like other ligand-gated ion channels, the GABA_A-ρ chloride channel is formed by oligomerization of five subunits arranged about a fivefold symmetry axis to form a central ion conducting pore. To date, three GABA_A-ρ receptor subunits have been identified in humans:

• ρ1 (GABRR1)
• ρ2 (GABRR2)
• ρ3 (GABRR3)

The above three subunits coassemble either to form functional homo-pentamers (ρ1₅, ρ2₅, ρ3₅) or hetero-pentamers (ρ1_mρ2_n, ρ2_mρ3_n where m + n = 5).^[18][19]

There is also evidence that ρ1 subunits can form hetero-pentameric complexes with GABA_A receptor γ2 subunits.^{[20][21][22][23]}

There are several pharmacological differences that distinguish GABA_A-ρ from GABA_A and GABA_B receptors.^[24] For example, GABA_A-ρ receptors are:

• selectively activated by (+)-CAMP [(+)-cis-2-aminomethylcyclopropane-carboxylic acid] and blocked by TPMPA [(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid];
• not sensitive to the GABA_B agonist baclofen nor the GABA_A receptor antagonist bicuculline;
• not modulated by many GABA_A receptor modulators such as barbiturates, benzodiazepines, and neuroactive steroids.

• CACA
• CAMP
• GABOB^[25]

Mixed GABA_A-ρ / GABA_B antagonists

• ZAPA ((Z)-3-[(Aminoiminomethyl)thio]prop-2-enoic acid)
• SKF-97541 (3-Aminopropyl(methyl)phosphinic acid)
• CGP-36742 (3-aminopropyl-n-butyl-phosphinic acid)

Selective GABA_A-ρ antagonists

• TPMPA
• (±)-cis-(3-Aminocyclopentyl)butylphosphinic acid
• (S)-(4-Aminocyclopent-1-enyl)butylphosphinic acid
• N₂O

In humans, GABA_A-ρ receptor subunits ρ1 and ρ2 are encoded by the GABRR1 and GABRR2 genes which are found on chromosome 6 whereas the GABRR3 gene for ρ3 is found on chromosome 3 Mutations in the ρ1 or ρ2 genes may be responsible for some cases of autosomal recessive retinitis pigmentosa.^[26]

• GABA_A receptor
• GABA_B receptor
• Gamma-aminobutyric acid