GABAA-rho receptor

A second type of ionotropic GABA receptor, insensitive to typical allosteric modulators of GABA_A receptor channels such as benzodiazepines and barbiturates,{{cite journal |vauthors=Sivilotti L, Nistri A | title = GABA receptor mechanisms in the central nervous system | journal = Prog. Neurobiol. | volume = 36 | issue = 1 | pages = 35–92 | year = 1991 | pmid = 1847747 | doi = 10.1016/0301-0082(91)90036-Z | s2cid = 31732465 }}{{cite journal |vauthors=Bormann J, Feigenspan A | title = GABAC receptors | journal = Trends Neurosci. | volume = 18 | issue = 12 | pages = 515–519 |date=December 1995 | pmid = 8638289 | doi = 10.1016/0166-2236(95)98370-E | s2cid = 40853254 }}{{cite journal | author = Johnston GA | title = GABAc receptors: relatively simple transmitter -gated ion channels? | journal = Trends Pharmacol. Sci. | volume = 17 | issue = 9 | pages = 319–323 |date=September 1996 | pmid = 8885697 | doi = 10.1016/0165-6147(96)10038-9 | doi-access = free }} was designated GABA_С receptor.{{cite journal | vauthors = Drew CA, Johnston GA, Weatherby RP | title = Bicuculline-insensitive GABA receptors: studies on the binding of (−)-baclofen to rat cerebellar membranes | journal = Neurosci. Lett. | volume = 52 | issue = 3 | pages = 317–321 |date=December 1984 | pmid = 6097844 | doi = 10.1016/0304-3940(84)90181-2 | s2cid = 966075 }}{{cite journal |vauthors=Zhang D, Pan ZH, Awobuluyi M, Lipton SA | title = Structure and function of GABA_C receptors: a comparison of native versus recombinant receptors | journal = Trends Pharmacol. Sci. | volume = 22 | issue = 3 | pages = 121–132 |date=March 2001 | pmid = 11239575 | doi = 10.1016/S0165-6147(00)01625-4 }} Native responses of the GABA_C receptor type occur in retinal bipolar or horizontal cells across vertebrate species.{{cite journal |vauthors=Feigenspan A, Wässle H, Bormann J | title = Pharmacology of GABA receptor Cl⁻ channels in rat retinal bipolar cells | journal = Nature | volume = 361 | issue = 6408 | pages = 159–162 |date=January 1993 | pmid = 7678450 | doi = 10.1038/361159a0 | bibcode = 1993Natur.361..159F | s2cid = 4347233 }}{{cite journal |vauthors=Qian H, Dowling JE | title = Novel GABA responses from rod-driven retinal horizontal cells | journal = Nature | volume = 361 | issue = 6408 | pages = 162–164 |date=January 1993 | pmid = 8421521 | doi = 10.1038/361162a0 | bibcode = 1993Natur.361..162Q | s2cid = 4320616 }}{{cite journal | author = Lukasiewicz PD | title = GABAC receptors in the vertebrate retina | journal = Mol. Neurobiol. | volume = 12 | issue = 3 | pages = 181–194 |date=June 1996 | pmid = 8884747 | doi = 10.1007/BF02755587 | s2cid = 37167159 }}{{cite journal |vauthors=Wegelius K, Pasternack M, Hiltunen JO, Rivera C, Kaila K, Saarma M, Reeben M | title = Distribution of GABA receptor rho subunit transcripts in the rat brain | journal = Eur. J. Neurosci. | volume = 10 | issue = 1 | pages = 350–357 |date=January 1998 | pmid = 9753143 | doi = 10.1046/j.1460-9568.1998.00023.x | s2cid = 25863134 }}

GABA_С receptors are exclusively composed of ρ (rho) subunits that are related to GABA_A receptor subunits.{{cite journal |vauthors=Shimada S, Cutting G, Uhl GR | title = 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 | journal = Mol. Pharmacol. | volume = 41 | issue = 4 | pages = 683–687 |date=April 1992 | pmid = 1314944 | url = http://molpharm.aspetjournals.org/cgi/reprint/41/4/683 }}{{cite journal |vauthors=Kusama T, Spivak CE, Whiting P, Dawson VL, Schaeffer JC, Uhl GR | title = Pharmacology of GABA ρ1 and GABA α/β receptors expressed in Xenopus oocytes and COS cells | journal = Br. J. Pharmacol. | volume = 109 | issue = 1 | pages = 200–206 |date=May 1993 | pmid = 8388298 | pmc = 2175610 | doi = 10.1111/j.1476-5381.1993.tb13554.x}}{{cite journal |vauthors=Kusama T, Wang TL, Guggino WB, Cutting GR, Uhl GR | title = GABA rho 2 receptor pharmacological profile: GABA recognition site similarities to rho 1 | journal = Eur. J. Pharmacol. | volume = 245 | issue = 1 | pages = 83–84 |date=March 1993 | pmid = 8386671 | doi = 10.1016/0922-4106(93)90174-8 }} Although the term "GABA_С receptor" is frequently used, GABA_С may be viewed as a variant within the GABA_A receptor family.{{cite journal |vauthors=Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ | title = International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function | journal = Pharmacol. Rev. | volume = 50 | issue = 2 | pages = 291–313 |date=June 1998 | pmid = 9647870 | url = http://pharmrev.aspetjournals.org/cgi/content/full/50/2/291 }} 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.{{cite journal |vauthors=Chebib M, Johnston GA | title = GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology | journal = J. Med. Chem. | volume = 43 | issue = 8 | pages = 1427–1447 |date=April 2000 | pmid = 10780899 | doi = 10.1021/jm9904349 }}{{cite journal | author = Bormann J | title = The 'ABC' of GABA receptors | journal = Trends Pharmacol. Sci. | volume = 21 | issue = 1 | pages = 16–19 |date=January 2000 | pmid = 10637650 | doi = 10.1016/S0165-6147(99)01413-3 }} 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).{{cite journal |vauthors=Olsen RW, Sieghart W | title = International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update | journal = Pharmacological Reviews | volume = 60 | issue = 3 | pages = 243–260 |date=September 2008 | pmid = 18790874 | pmc = 2847512 | doi = 10.1124/pr.108.00505 }}

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.{{Cite journal |last1=Naffaa |first1=Moawiah M. |last2=Hung |first2=Sandy |last3=Chebib |first3=Mary |last4=Johnston |first4=Graham A. R. |last5=Hanrahan |first5=Jane R. |date=July 2017 |title=GABA-ρ receptors: distinctive functions and molecular pharmacology |journal=Br J Pharmacol |volume=174 |issue=13 |pages=1881–1894 |doi=10.1111/bph.13768 |pmc=5466530 |pmid=28258627 |doi-access=free}}

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 ({{Gene|GABRR1}})
• ρ2 ({{Gene|GABRR2}})
• ρ3 ({{Gene|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).{{cite journal |vauthors=Enz R, Cutting GR |title=Molecular composition of GABAC receptors|journal= Vision Res |volume= 38 |issue= 10 |pages= 1431–1441 |year= 1998 |pmid= 9667009 | doi = 10.1016/S0042-6989(97)00277-0|s2cid=14457042|doi-access= }}{{cite journal |vauthors=Ogurusu T, Yanagi K, Watanabe M, Fukaya M, Shingai R |title=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|journal= Receptors Channels |volume= 6 |issue= 6 |pages= 463–475 |year= 1999 |pmid= 10635063 }}

There is also evidence that ρ1 subunits can form hetero-pentameric complexes with GABA_A receptor γ2 subunits.{{cite journal |vauthors=Qian H, Ripps H | title = Response kinetics and pharmacological properties of heteromeric receptors formed by coassembly of GABA ρ- and γ2-subunits | journal= Proceedings of the Royal Society B | volume= 266 | issue = 1436 | pages = 2419–2425 | year = 1999 | pmid = 10643085 | pmc = 1690471 | doi = 10.1098/rspb.1999.0941}}{{cite journal |vauthors=Milligan CJ, Buckley NJ, Garret M, Deuchars J, Deuchars SA | title = Evidence for inhibition mediated by coassembly of GABAA and GABAC receptor subunits in native central neurons | journal = Journal of Neuroscience | volume = 24 | issue = 33 | pages = 7241–7250 |date=August 2004 | pmid = 15317850 | doi = 10.1523/JNEUROSCI.1979-04.2004 | pmc = 6729776 | doi-access = free }}{{cite journal |vauthors=Pan Y, Qian H | title = Interactions between rho and gamma2 subunits of the GABA receptor | journal = Journal of Neurochemistry | volume = 94 | issue = 2 | pages = 482–490 |date=July 2005 | pmid = 15998298 | doi = 10.1111/j.1471-4159.2005.03225.x | s2cid = 19865977 | doi-access = free }}{{cite journal |vauthors=Sieghart W, Ernst M | title = Heterogeneity of GABAA receptors: Revived interest in the development of subtype-selective drugs | journal = Current Medicinal Chemistry | volume = 5 | issue = 3 | pages = 217–242 | year = 2005 | doi = 10.2174/1568015054863837 }}

There are several pharmacological differences that distinguish GABA_A-ρ from GABA_A and GABA_B receptors.{{cite journal |vauthors=Chebib M, Johnston GA |title=GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology|journal= J Med Chem |volume= 43 |issue= 8 |pages= 1427–1447 |year= 2000|doi=10.1021/jm9904349 |pmid= 10780899 }} 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 and benzodiazepines, but are modulated selectively by certain neuroactive steroids.Morris KD, Moorefield CN, Amin J. Differential modulation of the gamma-aminobutyric acid type C receptor by neuroactive steroids. Mol Pharmacol. 1999;56(4):752‐759

• CACA
• CAMP
• GABOB{{cite journal |vauthors=Hinton T, Chebib M, Johnston GA |title=Enantioselective actions of 4-amino-3-hydroxybutanoic acid and (3-amino-2-hydroxypropyl)methylphosphinic acid at recombinant GABA(C) receptors |journal=Bioorganic & Medicinal Chemistry Letters |volume=18 |issue=1 |pages=402–404 |date=January 2008 |pmid=17981464 |doi=10.1016/j.bmcl.2007.10.019 }}
• Muscimol

;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 {{Gene|GABRR1}} and {{Gene|GABRR2}} genes which are found on chromosome 6 whereas the {{Gene|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.{{cite journal |vauthors=Marcos I, Ruiz A, Blaschak CJ, Borrego S, Cutting GR, Antinolo G |title=Mutation analysis of GABRR1 and GABRR2 in autosomal recessive retinitis pigmentosa|journal= J Med Genet |volume= 37 |issue= 6 |pages= E5 |year= 1998 |pmid= 10851258 |pmc=1734609 | doi = 10.1136/jmg.37.6.e5}}

{{Reflist|2}}

{{Ligand-gated ion channels}}

{{GABAergics}}

{{DEFAULTSORT:Gabaa-Rho Receptor}}

Category:Transmembrane receptors

Category:GABA