GABAA-rho receptor

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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 GABAA-rho receptor (previously known as the GABAC receptor) is a subclass of GABAA receptors composed entirely of rho (ρ) subunits. GABAA 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 GABAAreceptor, like other GABAA receptors, is expressed in many areas of the brain, but in contrast to other GABAA receptors, the GABAA-ρ receptor has especially high expression in the retina.[1]

Nomenclature[edit]

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

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

Function[edit]

In addition to containing a GABA binding site, the GABAA-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 GABAA-ρ receptors is slow to initiate but sustained in duration. In contrast, the GABAA receptor current has a rapid onset and short duration. GABA is about 10 times more potent at GABAA-ρ than it is at most GABAA receptors.

Structure[edit]

Like other ligand-gated ion channels, the GABAA-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 GABAA-ρ receptor subunits have been identified in humans:

The above three subunits coassemble either to form functional homo-pentamers (ρ15, ρ25, ρ35) or hetero-pentamers (ρ1mρ2n, ρ2mρ3n where m + n = 5).[18][19]

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

Pharmacology[edit]

There are several pharmacological differences that distinguish GABAA-ρ from GABAA and GABAB receptors.[24] For example, GABAA-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 GABAB agonist baclofen nor the GABAA receptor antagonist bicuculline;
  • not modulated by many GABAA receptor modulators such as barbiturates, benzodiazepines, and neuroactive steroids.

Selective Ligands[edit]

Agonists[edit]

Antagonists[edit]

Mixed GABAA-ρ / GABAB 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 GABAA-ρ antagonists
  • TPMPA
  • (±)-cis-(3-Aminocyclopentyl)butylphosphinic acid
  • (S)-(4-Aminocyclopent-1-enyl)butylphosphinic acid

Genetics[edit]

In humans, GABAA-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]

References[edit]

  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 GABAC 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. 

See also[edit]