GABAA-rho receptor

gamma-aminobutyric acid (GABA) receptor, rho 1
Identifiers
Symbol	GABRR1
Entrez	2569
HUGO	4090
OMIM	137161
RefSeq	NM_002042
UniProt	P24046
Other data
Locus	Chr. 6 q14-q21

gamma-aminobutyric acid (GABA) receptor, rho 2
Identifiers
Symbol	GABRR2
Entrez	2570
HUGO	4091
OMIM	137162
RefSeq	NM_002043
UniProt	P28476
Other data
Locus	Chr. 6 q14-q21

gamma-aminobutyric acid (GABA) receptor, rho 3
Identifiers
Symbol	GABRR3
Entrez	200959
HUGO	17969
RefSeq	NM_001105580
UniProt	Q9UIV9
Other data
Locus	Chr. 3 q12.2

The GABA_A-rho receptor (previously known as the GABA_C receptor) is a subclass of GABA_A receptors composed entirely of rho (ρ) subunits. GABA_A receptors including those of the ρ-subclass are ligand-gated ion channels responsible for mediating the effects of gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the brain. The GABA_A-ρ receptor, like other GABA_A receptors, is expressed in many areas of the brain, but in contrast to other GABA_A receptors, the GABA_A-ρ receptor has especially high expression in the retina.^[1]

Nomenclature

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]

Function

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.

Structure

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]}

Pharmacology

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.

Selective Ligands

Agonists

• CACA
• CAMP
• GABOB^[25]

Antagonists

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

Genetics

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]

See also

• GABA_A receptor
• GABA_B receptor
• Gamma-aminobutyric acid

References

1. Qian H. 2000. GABAc receptors in the vertebrate retina. Retrieved on February 14, 2007.
2. Sivilotti L, Nistri A (1991). "GABA receptor mechanisms in the central nervous system". Prog. Neurobiol. 36 (1): 35–92. doi:10.1016/0301-0082(91)90036-Z. PMID 1847747.
3. Bormann J, Feigenspan A (December 1995). "GABAC receptors". Trends Neurosci. 18 (12): 515–9. doi:10.1016/0166-2236(95)98370-E. PMID 8638289.
4. Johnston GA (September 1996). "GABAc receptors: relatively simple transmitter -gated ion channels?". Trends Pharmacol. Sci. 17 (9): 319–23. doi:10.1016/0165-6147(96)10038-9. PMID 8885697.
5. Drew CA, Johnston GA, Weatherby RP (December 1984). "Bicuculline-insensitive GABA receptors: studies on the binding of (−)-baclofen to rat cerebellar membranes". Neurosci. Lett. 52 (3): 317–21. doi:10.1016/0304-3940(84)90181-2. PMID 6097844.
6. Zhang D, Pan ZH, Awobuluyi M, Lipton SA (March 2001). "Structure and function of GABA_C receptors: a comparison of native versus recombinant receptors". Trends Pharmacol. Sci. 22 (3): 121–32. doi:10.1016/S0165-6147(00)01625-4. PMID 11239575.
7. Feigenspan A, Wässle H, Bormann J (January 1993). "Pharmacology of GABA receptor Cl⁻ channels in rat retinal bipolar cells". Nature. 361 (6408): 159–62. doi:10.1038/361159a0. PMID 7678450.
8. Qian H, Dowling JE (January 1993). "Novel GABA responses from rod-driven retinal horizontal cells". Nature. 361 (6408): 162–4. doi:10.1038/361162a0. PMID 8421521.
9. Lukasiewicz PD (June 1996). "GABAC receptors in the vertebrate retina". Mol. Neurobiol. 12 (3): 181–94. doi:10.1007/BF02755587. PMID 8884747.
10. Wegelius K, Pasternack M, Hiltunen JO, Rivera C, Kaila K, Saarma M, Reeben M (January 1998). "Distribution of GABA receptor rho subunit transcripts in the rat brain". Eur. J. Neurosci. 10 (1): 350–7. doi:10.1046/j.1460-9568.1998.00023.x. PMID 9753143.
11. Shimada S, Cutting G, Uhl GR (April 1992). "gamma-Aminobutyric acid A or C receptor? gamma-Aminobutyric acid rho 1 receptor RNA induces bicuculline-, barbiturate-, and benzodiazepine-insensitive gamma-aminobutyric acid responses in Xenopus oocytes". Mol. Pharmacol. 41 (4): 683–7. PMID 1314944.
12. Kusama T, Spivak CE, Whiting P, Dawson VL, Schaeffer JC, Uhl GR (May 1993). "Pharmacology of GABA ρ1 and GABA α/β receptors expressed in Xenopus oocytes and COS cells". Br. J. Pharmacol. 109 (1): 200–6. doi:10.1111/j.1476-5381.1993.tb13554.x. PMC 2175610. PMID 8388298.
13. Kusama T, Wang TL, Guggino WB, Cutting GR, Uhl GR (March 1993). "GABA rho 2 receptor pharmacological profile: GABA recognition site similarities to rho 1". Eur. J. Pharmacol. 245 (1): 83–4. doi:10.1016/0922-4106(93)90174-8. PMID 8386671.
14. Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ (June 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): 291–313. PMID 9647870.
15. Chebib M, Johnston GA (April 2000). "GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology". J. Med. Chem. 43 (8): 1427–47. doi:10.1021/jm9904349. PMID 10780899.
16. Bormann J (January 2000). "The 'ABC' of GABA receptors". Trends Pharmacol. Sci. 21 (1): 16–9. doi:10.1016/S0165-6147(99)01413-3. PMID 10637650.
17. Olsen RW, Sieghart W (September 2008). "International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update". Pharmacological Reviews. 60 (3): 243–60. doi:10.1124/pr.108.00505. PMC 2847512. PMID 18790874.
18. Enz R, Cutting GR (1998). "Molecular composition of GABAC receptors". Vision Res. 38 (10): 1431–41. doi:10.1016/S0042-6989(97)00277-0. PMID 9667009.
19. Ogurusu T, Yanagi K, Watanabe M, Fukaya M, Shingai R (1999). "Localization of GABA receptor rho 2 and rho 3 subunits in rat brain and functional expression of homo-oligomeric rho 3 receptors and hetero-oligomeric rho 2 rho 3 receptors". Receptors Channels. 6 (6): 463–75. PMID 10635063.
20. Qian H, Ripps H (1999). "Response kinetics and pharmacological properties of heteromeric receptors formed by coassembly of GABA ρ- and γ2-subunits". Proceedings of the Royal Society B. 266 (1436): 2419–25. doi:10.1098/rspb.1999.0941. PMC 1690471. PMID 10643085.
21. Milligan CJ, Buckley NJ, Garret M, Deuchars J, Deuchars SA (August 2004). "Evidence for inhibition mediated by coassembly of GABAA and GABAC receptor subunits in native central neurons". Journal of Neuroscience. 24 (33): 7241–50. doi:10.1523/JNEUROSCI.1979-04.2004. PMID 15317850.
22. Pan Y, Qian H (July 2005). "Interactions between rho and gamma2 subunits of the GABA receptor". Journal of Neurochemistry. 94 (2): 482–90. doi:10.1111/j.1471-4159.2005.03225.x. PMID 15998298.
23. Sieghart W, Ernst M (2005). "Heterogeneity of GABAA receptors: Revived interest in the development of subtype-selective drugs". Current Medicinal Chemistry. 5 (3): 217–242. doi:10.2174/1568015054863837.
24. Chebib M, Johnston GA (2000). "GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology". J Med Chem. 43 (8): 1427–47. doi:10.1021/jm9904349. PMID 10780899.
25. Hinton T, Chebib M, Johnston GA (January 2008). "Enantioselective actions of 4-amino-3-hydroxybutanoic acid and (3-amino-2-hydroxypropyl)methylphosphinic acid at recombinant GABA(C) receptors". Bioorganic & Medicinal Chemistry Letters. 18 (1): 402–4. doi:10.1016/j.bmcl.2007.10.019. PMID 17981464.
26. Marcos I, Ruiz A, Blaschak CJ, Borrego S, Cutting GR, Antinolo G (1998). "Mutation analysis of GABRR1 and GABRR2 in autosomal recessive retinitis pigmentosa". J Med Genet. 37 (6): E5. doi:10.1136/jmg.37.6.e5. PMC 1734609. PMID 10851258.