Jump to content

GABAA-rho receptor: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous edit
Content deleted Content added
VisualWikitext
Citation bot (talk | contribs)
Bots
5,321,922 edits
Add: bibcode. | Use this bot. Report bugs. | Suggested by Whoop whoop pull up | Category:Genes on human chromosome 3 | #UCB_Category 629/718
ce
 
(10 intermediate revisions by 7 users not shown)
Line 1: Line 1:
{{Short description|Class of transport proteins}}
{{Short description|Class of transport proteins}}
{{DISPLAYTITLE:GABA<sub>A</sub>-rho receptor}}
{{DISPLAYTITLE:GABA<sub>A</sub>-rho receptor}}
{{cs1 config|name-list-style=vanc }}
{{infobox protein
{{infobox protein
| Name = [[GABRR1|gamma-aminobutyric acid (GABA) receptor, rho 1]]
| Name = [[GABRR1|gamma-aminobutyric acid (GABA) receptor, rho 1]]
Line 62: Line 63:


== Nomenclature ==
== Nomenclature ==
A second type of [[ionotropic]] GABA receptor, insensitive to typical [[Allosteric regulation|allosteric modulators]] of GABA<sub>A</sub> receptor channels such as [[benzodiazepine]]s and [[barbiturate]]s,<ref name="pmid1847747">{{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 }}</ref><ref name="pmid8638289">{{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 }}</ref><ref name="pmid8885697">{{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 }}</ref> was designated GABA<sub>С</sub> receptor.<ref name="pmid6097844">{{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 }}</ref><ref name="pmid11239575">{{cite journal |vauthors=Zhang D, Pan ZH, Awobuluyi M, Lipton SA | title = Structure and function of GABA<sub>C</sub> 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 }}</ref> Native responses of the GABA<sub>C</sub> receptor type occur in [[retina]]l bipolar or horizontal cells across vertebrate species.<ref name="pmid7678450">{{cite journal |vauthors=Feigenspan A, Wässle H, Bormann J | title = Pharmacology of GABA receptor Cl<sup>−</sup> 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 }}</ref><ref name="pmid8421521">{{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 }}</ref><ref name="pmid8884747">{{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 }}</ref><ref name="pmid9753143">{{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 }}</ref>
A second type of [[ionotropic]] GABA receptor, insensitive to typical [[Allosteric regulation|allosteric modulators]] of GABA<sub>A</sub> receptor channels such as [[benzodiazepine]]s and [[barbiturate]]s,<ref name="pmid1847747">{{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 }}</ref><ref name="pmid8638289">{{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 }}</ref><ref name="pmid8885697">{{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 }}</ref> was designated GABA<sub>С</sub> receptor.<ref name="pmid6097844">{{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 }}</ref><ref name="pmid11239575">{{cite journal |vauthors=Zhang D, Pan ZH, Awobuluyi M, Lipton SA | title = Structure and function of GABA<sub>C</sub> 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 }}</ref> Native responses of the GABA<sub>C</sub> receptor type occur in [[retina]]l bipolar or horizontal cells across vertebrate species.<ref name="pmid7678450">{{cite journal |vauthors=Feigenspan A, Wässle H, Bormann J | title = Pharmacology of GABA receptor Cl<sup>−</sup> 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 }}</ref><ref name="pmid8421521">{{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 }}</ref><ref name="pmid8884747">{{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 }}</ref><ref name="pmid9753143">{{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 }}</ref>


GABA<sub>С</sub> receptors are exclusively composed of ρ (rho) subunits that are related to GABA<sub>A</sub> receptor subunits.<ref name="pmid1314944">{{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 }}</ref><ref name="pmid8388298">{{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}}</ref><ref name="pmid8386671">{{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 }}</ref> Although the term "GABA<sub>С</sub> receptor" is frequently used, GABA<sub>С</sub> may be viewed as a variant within the GABA<sub>A</sub> receptor family.<ref name="Barnard">{{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 }}</ref> Others have argued that the differences between GABA<sub>С</sub> and GABA<sub>A</sub> receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors.<ref name="pmid10780899">{{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 }}</ref><ref name="pmid10637650">{{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 }}</ref> However, since GABA<sub>С</sub> receptors are closely related in sequence, structure, and function to GABA<sub>A</sub> receptors and since other GABA<sub>A</sub> receptors besides those containing ρ subunits appear to exhibit GABA<sub>С</sub> pharmacology, the Nomenclature Committee of the [[International Union of Basic and Clinical Pharmacology|IUPHAR]] has recommended that the GABA<sub>С</sub> term no longer be used and these ρ receptors should be designated as the ρ subfamily of the GABA<sub>A</sub> receptors (GABA<sub>A</sub>-ρ).<ref name="pmid18790874">{{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 }}</ref>
GABA<sub>С</sub> receptors are exclusively composed of ρ (rho) subunits that are related to GABA<sub>A</sub> receptor subunits.<ref name="pmid1314944">{{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 }}</ref><ref name="pmid8388298">{{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}}</ref><ref name="pmid8386671">{{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 }}</ref> Although the term "GABA<sub>С</sub> receptor" is frequently used, GABA<sub>С</sub> may be viewed as a variant within the GABA<sub>A</sub> receptor family.<ref name="Barnard">{{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 }}</ref> Others have argued that the differences between GABA<sub>С</sub> and GABA<sub>A</sub> receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors.<ref name="pmid10780899">{{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 }}</ref><ref name="pmid10637650">{{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 }}</ref> However, since GABA<sub>С</sub> receptors are closely related in sequence, structure, and function to GABA<sub>A</sub> receptors and since other GABA<sub>A</sub> receptors besides those containing ρ subunits appear to exhibit GABA<sub>С</sub> pharmacology, the Nomenclature Committee of the [[International Union of Basic and Clinical Pharmacology|IUPHAR]] has recommended that the GABA<sub>С</sub> term no longer be used and these ρ receptors should be designated as the ρ subfamily of the GABA<sub>A</sub> receptors (GABA<sub>A</sub>-ρ).<ref name="pmid18790874">{{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 }}</ref>


== Function ==
== Function ==
In addition to containing a GABA binding site, the GABA<sub>A</sub>-ρ receptor complex conducts [[chloride]] ions across neuronal [[cell membrane|membrane]]s. 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<sub>A</sub>-ρ receptors is slow to initiate but sustained in duration. In contrast, the GABA<sub>A</sub> receptor current has a rapid onset and short duration. GABA is about 10 times more potent at GABA<sub>A</sub>-ρ than it is at most GABA<sub>A</sub> receptors.{{citation needed|date=May 2016}}
In addition to containing a GABA binding site, the GABA<sub>A</sub>-ρ receptor complex conducts [[chloride]] ions across neuronal [[cell membrane|membrane]]s. 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<sub>A</sub>-ρ receptors is slow to initiate but sustained in duration. In contrast, the GABA<sub>A</sub> receptor current has a rapid onset and short duration. GABA is about 10 times more potent at GABA<sub>A</sub>-ρ than it is at most GABA<sub>A</sub> receptors.<ref name="renamed_from_28258627_on_20240928002243">{{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}}</ref>


== Structure ==
== Structure ==
Line 74: Line 75:
* [[GABRR2|ρ2]] ({{Gene|GABRR2}})
* [[GABRR2|ρ2]] ({{Gene|GABRR2}})
* [[GABRR3|ρ3]] ({{Gene|GABRR3}})
* [[GABRR3|ρ3]] ({{Gene|GABRR3}})
The above three subunits coassemble either to form functional homo-pentamers (ρ1<sub>5</sub>, ρ2<sub>5</sub>, ρ3<sub>5</sub>) or hetero-pentamers (ρ1<sub>m</sub>ρ2<sub>n</sub>, ρ2<sub>m</sub>ρ3<sub>n</sub> where m + n = 5).<ref name="Enz">{{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= free }}</ref><ref name="Ogurusu">{{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 }}</ref>
The above three subunits coassemble either to form functional homo-pentamers (ρ1<sub>5</sub>, ρ2<sub>5</sub>, ρ3<sub>5</sub>) or hetero-pentamers (ρ1<sub>m</sub>ρ2<sub>n</sub>, ρ2<sub>m</sub>ρ3<sub>n</sub> where m + n = 5).<ref name="Enz">{{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= }}</ref><ref name="Ogurusu">{{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 }}</ref>


There is also evidence that ρ1 subunits can form hetero-pentameric complexes with [[GABAA receptor|GABA<sub>A</sub> receptor]] [[GABRG2|γ2 subunits]].<ref name="Qian">{{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}}</ref><ref name="pmid15317850">{{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 }}</ref><ref name="pmid15998298">{{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 }}</ref><ref name="Sieghart_Ernst_2005">{{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 }}</ref>
There is also evidence that ρ1 subunits can form hetero-pentameric complexes with [[GABAA receptor|GABA<sub>A</sub> receptor]] [[GABRG2|γ2 subunits]].<ref name="Qian">{{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}}</ref><ref name="pmid15317850">{{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 }}</ref><ref name="pmid15998298">{{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 }}</ref><ref name="Sieghart_Ernst_2005">{{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 }}</ref>


== Pharmacology ==
== Pharmacology ==
Line 89: Line 90:
* [[(+)-cis-2-Aminomethylcyclopropane carboxylic acid|CAMP]]
* [[(+)-cis-2-Aminomethylcyclopropane carboxylic acid|CAMP]]
* [[GABOB]]<ref name="pmid17981464">{{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 }}</ref>
* [[GABOB]]<ref name="pmid17981464">{{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 }}</ref>
* [[Muscimol]]


=== Antagonists ===
=== Antagonists ===
Line 103: Line 105:


== Genetics ==
== Genetics ==
In humans, GABA<sub>A</sub>-ρ receptor subunits ρ1 and ρ2 are [[Codon|encoded by]] the {{Gene|GABRR1}} and {{Gene|GABRR2}} [[gene]]s which are found on [[Chromosome 6 (human)|chromosome 6]] whereas the {{Gene|GABRR3}} gene for ρ3 is found on [[Chromosome 3 (human)|chromosome 3]] Mutations in the ρ1 or ρ2 genes may be responsible for some cases of [[autosomal recessive]] [[retinitis pigmentosa]].<ref name="Marcos">{{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}}</ref>
In humans, GABA<sub>A</sub>-ρ receptor subunits ρ1 and ρ2 are [[Codon|encoded by]] the {{Gene|GABRR1}} and {{Gene|GABRR2}} [[gene]]s which are found on [[Chromosome 6 (human)|chromosome 6]] whereas the {{Gene|GABRR3}} gene for ρ3 is found on [[Chromosome 3 (human)|chromosome 3]]. Mutations in the ρ1 or ρ2 genes may be responsible for some cases of [[autosomal recessive]] [[retinitis pigmentosa]].<ref name="Marcos">{{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}}</ref>


== References ==
== References ==

Latest revision as of 04:15, 27 October 2024

gamma-aminobutyric acid (GABA) receptor, rho 1
Identifiers
SymbolGABRR1
NCBI gene2569
HGNC4090
OMIM137161
RefSeqNM_002042
UniProtP24046
Other data
LocusChr. 6 q14-q21
Search for
StructuresSwiss-model
DomainsInterPro
gamma-aminobutyric acid (GABA) receptor, rho 2
Identifiers
SymbolGABRR2
NCBI gene2570
HGNC4091
OMIM137162
RefSeqNM_002043
UniProtP28476
Other data
LocusChr. 6 q14-q21
Search for
StructuresSwiss-model
DomainsInterPro
gamma-aminobutyric acid (GABA) receptor, rho 3
Identifiers
SymbolGABRR3
NCBI gene200959
HGNC17969
RefSeqNM_001105580
UniProtQ9UIV9
Other data
LocusChr. 3 q12.2
Search for
StructuresSwiss-model
DomainsInterPro

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 GABAA-ρ receptor, 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 recommended 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.[18]

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).[19][20]

There is also evidence that ρ1 subunits can form hetero-pentameric complexes with GABAA receptor γ2 subunits.[21][22][23][24]

Pharmacology

[edit]

There are several pharmacological differences that distinguish GABAA-ρ from GABAA and GABAB receptors.[25] 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 and benzodiazepines, but are modulated selectively by certain neuroactive steroids.[26]

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
  • N2O

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.[28]

References

[edit]
  1. ^ Qian H. 2000. GABAc receptors in the vertebrate retina Archived 2010-12-31 at the Wayback Machine. 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. S2CID 31732465.
  3. ^ Bormann J, Feigenspan A (December 1995). "GABAC receptors". Trends Neurosci. 18 (12): 515–519. doi:10.1016/0166-2236(95)98370-E. PMID 8638289. S2CID 40853254.
  4. ^ Johnston GA (September 1996). "GABAc receptors: relatively simple transmitter -gated ion channels?". Trends Pharmacol. Sci. 17 (9): 319–323. 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): 317–321. doi:10.1016/0304-3940(84)90181-2. PMID 6097844. S2CID 966075.
  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): 121–132. 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): 159–162. Bibcode:1993Natur.361..159F. doi:10.1038/361159a0. PMID 7678450. S2CID 4347233.
  8. ^ Qian H, Dowling JE (January 1993). "Novel GABA responses from rod-driven retinal horizontal cells". Nature. 361 (6408): 162–164. Bibcode:1993Natur.361..162Q. doi:10.1038/361162a0. PMID 8421521. S2CID 4320616.
  9. ^ Lukasiewicz PD (June 1996). "GABAC receptors in the vertebrate retina". Mol. Neurobiol. 12 (3): 181–194. doi:10.1007/BF02755587. PMID 8884747. S2CID 37167159.
  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): 350–357. doi:10.1046/j.1460-9568.1998.00023.x. PMID 9753143. S2CID 25863134.
  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): 683–687. 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): 200–206. 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): 83–84. 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): 1427–1447. doi:10.1021/jm9904349. PMID 10780899.
  16. ^ Bormann J (January 2000). "The 'ABC' of GABA receptors". Trends Pharmacol. Sci. 21 (1): 16–19. 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): 243–260. doi:10.1124/pr.108.00505. PMC 2847512. PMID 18790874.
  18. ^ Naffaa MM, Hung S, Chebib M, Johnston GA, Hanrahan JR (July 2017). "GABA-ρ receptors: distinctive functions and molecular pharmacology". Br J Pharmacol. 174 (13): 1881–1894. doi:10.1111/bph.13768. PMC 5466530. PMID 28258627.
  19. ^ Enz R, Cutting GR (1998). "Molecular composition of GABAC receptors". Vision Res. 38 (10): 1431–1441. doi:10.1016/S0042-6989(97)00277-0. PMID 9667009. S2CID 14457042.
  20. ^ 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): 463–475. PMID 10635063.
  21. ^ 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): 2419–2425. doi:10.1098/rspb.1999.0941. PMC 1690471. PMID 10643085.
  22. ^ 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): 7241–7250. doi:10.1523/JNEUROSCI.1979-04.2004. PMC 6729776. PMID 15317850.
  23. ^ Pan Y, Qian H (July 2005). "Interactions between rho and gamma2 subunits of the GABA receptor". Journal of Neurochemistry. 94 (2): 482–490. doi:10.1111/j.1471-4159.2005.03225.x. PMID 15998298. S2CID 19865977.
  24. ^ 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.
  25. ^ Chebib M, Johnston GA (2000). "GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology". J Med Chem. 43 (8): 1427–1447. doi:10.1021/jm9904349. PMID 10780899.
  26. ^ 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
  27. ^ 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): 402–404. doi:10.1016/j.bmcl.2007.10.019. PMID 17981464.
  28. ^ 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.
Retrieved from "https://en.wikipedia.org/w/index.php?title=GABAA-rho_receptor&oldid=1253651726"