GABRA3: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
m (Bot: HTTP→HTTPS)
imported>Citation bot
m (Alter: journal. Add: pmc, pmid, doi. Removed parameters. You can use this bot yourself. Report bugs here. | Anas1712)
 
Line 1: Line 1:
{{Infobox_gene}}
{{Infobox_gene}}
'''Gamma-aminobutyric acid receptor subunit alpha-3''' is a [[protein]] that in humans is encoded by the ''GABRA3'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: GABRA3 gamma-aminobutyric acid (GABA) A receptor, alpha 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2556| accessdate = }}</ref>
'''Gamma-aminobutyric acid receptor subunit alpha-3''' is a [[protein]] that in humans is encoded by the ''GABRA3'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: GABRA3 gamma-aminobutyric acid (GABA) A receptor, alpha 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2556| access-date = }}</ref>


== Function ==
== Function ==


[[GABA]] is the major inhibitory neurotransmitter in the mammalian brain where it acts at [[GABAA receptor|GABA<sub>A</sub> receptors]], which are ligand-gated [[chloride channel]]s. Chloride conductance of these channels can be modulated by agents such as [[benzodiazepine]]s that bind to the GABA<sub>A</sub> receptor. At least 16 distinct subunits of GABA-A receptors have been identified.<ref name="entrez" /> GABA receptors are composed of 5 subunits with an extracellular ligand binding domains and ion channel domains that are integral to the membrane.Ligand binding to these receptors activates the channel.<ref name="pmid12069787">{{cite journal |vauthors=Cromer BA, Morton CJ, Parker MW | title = Anxiety over GABA(A) receptor structure relieved by AChBP | journal = Trends Biochem. Sci. | volume = 27 | issue = 6 | pages = 280–7 |date=June 2002 | pmid = 12069787 | doi = 10.1016/S0968-0004(02)02092-3 | url = | issn = }}</ref>
[[GABA]] is the major inhibitory neurotransmitter in the mammalian brain where it acts at [[GABAA receptor|GABA<sub>A</sub> receptors]], which are ligand-gated [[chloride channel]]s. Chloride conductance of these channels can be modulated by agents such as [[benzodiazepine]]s that bind to the GABA<sub>A</sub> receptor. At least 16 distinct subunits of GABA-A receptors have been identified.<ref name="entrez" /> GABA receptors are composed of 5 subunits with an extracellular ligand binding domains and ion channel domains that are integral to the membrane.Ligand binding to these receptors activates the channel.<ref name="pmid12069787">{{cite journal | vauthors = Cromer BA, Morton CJ, Parker MW | title = Anxiety over GABA(A) receptor structure relieved by AChBP | journal = Trends in Biochemical Sciences | volume = 27 | issue = 6 | pages = 280–7 | date = June 2002 | pmid = 12069787 | doi = 10.1016/S0968-0004(02)02092-3 }}</ref>


== Subunit selective ligands ==
== Subunit selective ligands ==


Recent research has produced several ligands that are moderately selective for GABA<sub>A</sub> receptors containing the α<sub>3</sub> subunit. Subtype-selective agonists for α<sub>3</sub> produce [[anxiolytic]] and mild [[sedative]] effects, but without causing [[amnesia]] or [[ataxia]], which could make them superior to currently marketed drugs.
Recent research has produced several ligands that are selective for GABA<sub>A</sub> receptors containing the α<sub>3</sub> subunit. Subtype-selective agonists for α<sub>3</sub> produce [[anxiolytic]] effects without [[sedative]], [[amnesia]], [[ataxia]]. <ref name="a3">{{cite journal |vauthors=Fischer BD, Atack JR, Platt DM, etal |title=Contribution of GABAA receptors containing α3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys |journal=Psychopharmacology |volume=215 |issue=2 |pages=311–319 |date=2011|doi=10.1007/s00213-010-2142-y |pmid=21190016 |pmc=3097109 }}</ref>
selective a<sub>3</sub> agonists also show lack of [[Substance dependence|dependence]], <ref name="dependence">{{cite journal |vauthors = Cheng T, Wallace D, Ponteri B, et al | title = Valium without dependence? Individual GABAA receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects | url = https://www.dovepress.com/valium-without-dependence-individual-gabaa-receptor-subtype-contributi-peer-reviewed-fulltext-article-NDT | journal = Neuropsychiatr. Dis. Treat.| volume = 14 | pages = 1351–1361 | date = 2018| pmid = 29872302 | pmc = 5973310 | doi = 10.2147/NDT.S164307 }}</ref> and could make them superior to currently marketed drugs.


=== Agonists ===
=== Agonists ===
Line 14: Line 15:
* [[Adipiplon]]
* [[Adipiplon]]
* [[PWZ-029]] (partial agonist at α<sub>3</sub>, partial inverse agonist at α<sub>5</sub>)
* [[PWZ-029]] (partial agonist at α<sub>3</sub>, partial inverse agonist at α<sub>5</sub>)
* [[TP003]] (Selective full agonist at α<sub>3</sub>)


=== Inverse agonists ===
=== Inverse agonists ===
Line 48: Line 50:
The GABRA3 transcript undergoes [[pre-mRNA]] editing by the [[ADAR]] family of enzymes.<ref name="pmid17369310"/> [[RNA editing#A-I editing|A-to-I editing]] changes an [[isoleucine]] codon to code for a [[methionine]] residue. This editing is thought to be important for [[brain development]], as the level of editing is low at birth and becomes almost 100% in an adult brain.<ref name="pmid17369310"/>
The GABRA3 transcript undergoes [[pre-mRNA]] editing by the [[ADAR]] family of enzymes.<ref name="pmid17369310"/> [[RNA editing#A-I editing|A-to-I editing]] changes an [[isoleucine]] codon to code for a [[methionine]] residue. This editing is thought to be important for [[brain development]], as the level of editing is low at birth and becomes almost 100% in an adult brain.<ref name="pmid17369310"/>


The editing occurs in an RNA [[stem-loop]] found in [[exon]] 9.<ref name="pmid17369310"/> The structured loci was identified using a specialised [[bioinformatics]] screen<ref name="pmid16257978">{{cite journal |vauthors=Ohlson J, Ensterö M, Sjöberg BM, Ohman M | title = A method to find tissue-specific novel sites of selective adenosine deamination | journal = Nucleic Acids Res. | volume = 33 | issue = 19 | pages = e167 | year = 2005 | pmid = 16257978 | pmc = 1275595 | doi = 10.1093/nar/gni169 | url = | issn = }}</ref> of the human genome. The proposed function of the edit is to alter [[chloride]] permeability of the [[GABA receptor]].<ref name="pmid17369310"/>
The editing occurs in an RNA [[stem-loop]] found in [[exon]] 9.<ref name="pmid17369310"/> The structured loci was identified using a specialised [[bioinformatics]] screen<ref name="pmid16257978">{{cite journal | vauthors = Ohlson J, Ensterö M, Sjöberg BM, Ohman M | title = A method to find tissue-specific novel sites of selective adenosine deamination | journal = Nucleic Acids Research | volume = 33 | issue = 19 | pages = e167 | date = October 2005 | pmid = 16257978 | pmc = 1275595 | doi = 10.1093/nar/gni169 }}</ref> of the human genome. The proposed function of the edit is to alter [[chloride]] permeability of the [[GABA receptor]].<ref name="pmid17369310"/>


At the time of discovery, [[Kv1.1]] mRNA was the only previously known [[mammalia]]n coding site containing both the edit sequence and the editing complementary sequence.<ref name="pmid15361858">{{cite journal |vauthors=Bhalla T, Rosenthal JJ, Holmgren M, Reenan R | title = Control of human potassium channel inactivation by editing of a small mRNA hairpin | journal = Nat. Struct. Mol. Biol. | volume = 11 | issue = 10 | pages = 950–6 |date=October 2004 | pmid = 15361858 | doi = 10.1038/nsmb825 | url = | issn = }}</ref>
At the time of discovery, [[Kv1.1]] mRNA was the only previously known [[mammalia]]n coding site containing both the edit sequence and the editing complementary sequence.<ref name="pmid15361858">{{cite journal | vauthors = Bhalla T, Rosenthal JJ, Holmgren M, Reenan R | title = Control of human potassium channel inactivation by editing of a small mRNA hairpin | journal = Nature Structural & Molecular Biology | volume = 11 | issue = 10 | pages = 950–6 | date = October 2004 | pmid = 15361858 | doi = 10.1038/nsmb825 }}</ref>


=== Type ===
=== Type ===
Line 58: Line 60:
=== Location ===
=== Location ===


The editing site was previously believed to be a single nucleotide polymorphism.<ref name="pmid14613934">{{cite journal |vauthors=Wang Q, Miyakoda M, Yang W, Khillan J, Stachura DL, Weiss MJ, Nishikura K | title = Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene | journal = J. Biol. Chem. | volume = 279 | issue = 6 | pages = 4952–61 |date=February 2004 | pmid = 14613934 | doi = 10.1074/jbc.M310162200 | url = | issn = }}</ref> The editing site is found at amino acid 5 of transmembrane domain 3 of exon 9. The predicted double-stranded RNA structure is interrupted by three bulges and a mismatch at the editing site.  The double-stranded region is 22 base pairs in length. As with editing of the KCNA1 gene product,<ref name="pmid15361858" /> the editing region and the editing complementary sequence are both found in exonic regions. In the pre=mRNA of GABRA3, both are found within exon 9.<ref name="pmid17369310">{{cite journal |vauthors=Ohlson J, Pedersen JS, Haussler D, Ohman M | title = Editing modifies the GABA(A) receptor subunit alpha3 | journal = RNA | volume = 13 | issue = 5 | pages = 698–703 |date=May 2007 | pmid = 17369310 | pmc = 1852825 | doi = 10.1261/rna.349107 | url = | issn = }}</ref> The other subunits of the receptor are thought not to be edited, as their predicted secondary structure is less likely to be edited. Also, alpha subunits 1 and 6 have a uridine instead of an adenosine at the site corresponding to the editing site in alpha subunit 3.<ref name="pmid17369310"/> Point mutation experiments determined that a Cytidine 15 nucleotides from the editing site is the base opposite the edited base.<ref name="pmid17369310"/> Using a GABRA3 mini-gene that encodes for exon 9 cotransfected to HEK293 cells with either ADAR1 or -2 or none, it was determined that both active ADARs can efficiently edited the site in exon 9.<ref name="pmid17369310"/>
The editing site was previously believed to be a single nucleotide polymorphism.<ref name="pmid14613934">{{cite journal | vauthors = Wang Q, Miyakoda M, Yang W, Khillan J, Stachura DL, Weiss MJ, Nishikura K | title = Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene | journal = The Journal of Biological Chemistry | volume = 279 | issue = 6 | pages = 4952–61 | date = February 2004 | pmid = 14613934 | doi = 10.1074/jbc.M310162200 }}</ref> The editing site is found at amino acid 5 of transmembrane domain 3 of exon 9. The predicted double-stranded RNA structure is interrupted by three bulges and a mismatch at the editing site.  The double-stranded region is 22 base pairs in length. As with editing of the KCNA1 gene product,<ref name="pmid15361858" /> the editing region and the editing complementary sequence are both found in exonic regions. In the pre=mRNA of GABRA3, both are found within exon 9.<ref name="pmid17369310">{{cite journal | vauthors = Ohlson J, Pedersen JS, Haussler D, Ohman M | title = Editing modifies the GABA(A) receptor subunit alpha3 | journal = RNA | volume = 13 | issue = 5 | pages = 698–703 | date = May 2007 | pmid = 17369310 | pmc = 1852825 | doi = 10.1261/rna.349107 }}</ref> The other subunits of the receptor are thought not to be edited, as their predicted secondary structure is less likely to be edited. Also, alpha subunits 1 and 6 have a uridine instead of an adenosine at the site corresponding to the editing site in alpha subunit 3.<ref name="pmid17369310"/> Point mutation experiments determined that a Cytidine 15 nucleotides from the editing site is the base opposite the edited base.<ref name="pmid17369310"/> Using a GABRA3 mini-gene that encodes for exon 9 cotransfected to HEK293 cells with either ADAR1 or -2 or none, it was determined that both active ADARs can efficiently edited the site in exon 9.<ref name="pmid17369310"/>


=== Regulation ===
=== Regulation ===


The mRNA expression of the alpha 3 subunit is developmentally regulated.  It is the dominant subunit in the forebrain tissue at birth, gradually decreasing in prominence as alpha subunit 1 takes over. Also experiments with mice have demonstrated that editing of pre-mRNA alpha 3 subunit increases from 50% at birth to nearly 100% in adult.<ref name="pmid17369310"/> Editing levels are lower in the hippocampus<ref name="pmid18550761">{{cite journal |vauthors=Rula EY, Lagrange AH, Jacobs MM, Hu N, Macdonald RL, Emeson RB | title = Developmental modulation of GABA(A) receptor function by RNA editing | journal = J. Neurosci. | volume = 28 | issue = 24 | pages = 6196–201 |date=June 2008 | pmid = 18550761 | pmc = 2746000 | doi = 10.1523/JNEUROSCI.0443-08.2008 | url = | issn = }}</ref>
The mRNA expression of the alpha 3 subunit is developmentally regulated.  It is the dominant subunit in the forebrain tissue at birth, gradually decreasing in prominence as alpha subunit 1 takes over. Also experiments with mice have demonstrated that editing of pre-mRNA alpha 3 subunit increases from 50% at birth to nearly 100% in adult.<ref name="pmid17369310"/> Editing levels are lower in the hippocampus<ref name="pmid18550761">{{cite journal | vauthors = Rula EY, Lagrange AH, Jacobs MM, Hu N, Macdonald RL, Emeson RB | title = Developmental modulation of GABA(A) receptor function by RNA editing | journal = The Journal of Neuroscience | volume = 28 | issue = 24 | pages = 6196–201 | date = June 2008 | pmid = 18550761 | pmc = 2746000 | doi = 10.1523/JNEUROSCI.0443-08.2008 }}</ref>


=== Conservation ===
=== Conservation ===


At the location corresponding to the I/M site of GABRA3 in frog and pufferfish there is a genomically encoded methionine.  In all other species, there is an isoleucine at the position.<ref name="pmid16381938">{{cite journal |vauthors=Hinrichs AS, Karolchik D, Baertsch R, Barber GP, Bejerano G, Clawson H, Diekhans M, Furey TS, Harte RA, Hsu F, Hillman-Jackson J, Kuhn RM, Pedersen JS, Pohl A, Raney BJ, Rosenbloom KR, Siepel A, Smith KE, Sugnet CW, Sultan-Qurraie A, Thomas DJ, Trumbower H, Weber RJ, Weirauch M, Zweig AS, Haussler D, Kent WJ | title = The UCSC Genome Browser Database: update 2006 | journal = Nucleic Acids Res. | volume = 34 | issue = Database issue | pages = D590–8 |date=January 2006 | pmid = 16381938 | pmc = 1347506 | doi = 10.1093/nar/gkj144 | url = | issn = }}</ref>
At the location corresponding to the I/M site of GABRA3 in frog and pufferfish there is a genomically encoded methionine.  In all other species, there is an isoleucine at the position.<ref name="pmid16381938">{{cite journal | vauthors = Hinrichs AS, Karolchik D, Baertsch R, Barber GP, Bejerano G, Clawson H, Diekhans M, Furey TS, Harte RA, Hsu F, Hillman-Jackson J, Kuhn RM, Pedersen JS, Pohl A, Raney BJ, Rosenbloom KR, Siepel A, Smith KE, Sugnet CW, Sultan-Qurraie A, Thomas DJ, Trumbower H, Weber RJ, Weirauch M, Zweig AS, Haussler D, Kent WJ | title = The UCSC Genome Browser Database: update 2006 | journal = Nucleic Acids Research | volume = 34 | issue = Database issue | pages = D590–8 | date = January 2006 | pmid = 16381938 | pmc = 1347506 | doi = 10.1093/nar/gkj144 }}</ref>


=== Consequences ===
=== Consequences ===
Line 72: Line 74:
==== Structure ====
==== Structure ====


Editing results in a codon change from (AUA)I to (AUG)M at the editing site.  This results in translation of a methionine instead of an isoleucine at the I/M site.  The amino acid change occurs in the transmembrane domain 3. The 4 transmembrane domains of each of the 5 subunits that make up the receptor interact to form the receptor channel.  It is likely that the change of amino acids disturbs the structure, effecting gating and inactivation of the channel.<ref name="pmid14996540">{{cite journal | author = Fisher JL | title = A mutation in the GABAA receptor alpha 1 subunit linked to human epilepsy affects channel gating properties | journal = Neuropharmacology | volume = 46 | issue = 5 | pages = 629–37 |date=April 2004 | pmid = 14996540 | doi = 10.1016/j.neuropharm.2003.11.015 | url = | issn = }}</ref> This is because methionine has a larger side chain.<ref name="pmid17369310"/>
Editing results in a codon change from (AUA)I to (AUG)M at the editing site.  This results in translation of a methionine instead of an isoleucine at the I/M site.  The amino acid change occurs in the transmembrane domain 3. The 4 transmembrane domains of each of the 5 subunits that make up the receptor interact to form the receptor channel.  It is likely that the change of amino acids disturbs the structure, effecting gating and inactivation of the channel.<ref name="pmid14996540">{{cite journal | vauthors = Fisher JL | title = A mutation in the GABAA receptor alpha 1 subunit linked to human epilepsy affects channel gating properties | journal = Neuropharmacology | volume = 46 | issue = 5 | pages = 629–37 | date = April 2004 | pmid = 14996540 | doi = 10.1016/j.neuropharm.2003.11.015 }}</ref> This is because methionine has a larger side chain.<ref name="pmid17369310"/>


==== Function ====
==== Function ====


While the effect of editing on protein function is unknown, the developmental increase in editing does correspond to changes in function of the GAGA<sub>A</sub> receptor. GABA binding leads to chloride channel activation, resulting in rapid increase in concentration of the ion. Initially, the receptor is an excitatory receptor, mediating depolarisation (efflux of Cl<sup>−</sup> ions) in immature neurons before changing to an inhibitory receptor, mediating hyperpolarisation(influx of Cl<sup>−</sup> ions) later on.<ref name="pmid12209121">{{cite journal | author = Ben-Ari Y | title = Excitatory actions of gaba during development: the nature of the nurture | journal = Nat. Rev. Neurosci. | volume = 3 | issue = 9 | pages = 728–39 |date=September 2002 | pmid = 12209121 | doi = 10.1038/nrn920 | url = | issn = }}</ref> GABA<sub>A</sub> converts to an inhibitory receptor from an excitatory receptor by the upregulation of [[SLC12A5|KCC2]] cotransporter. This decreases the concentration of Cl<sup>−</sup> ion within cells. Therefore, the GAGA<sub>A</sub> subunits are involved in determining the nature of the receptor in response to GABA ligand.<ref name="pmid15199051">{{cite journal |vauthors=Böhme I, Rabe H, Lüddens H | title = Four amino acids in the alpha subunits determine the gamma-aminobutyric acid sensitivities of GABAA receptor subtypes | journal = J. Biol. Chem. | volume = 279 | issue = 34 | pages = 35193–200 |date=August 2004 | pmid = 15199051 | doi = 10.1074/jbc.M405653200 | url = | issn = }}</ref> These changes suggest that editing of the subunit is important in the developing brain by regulating the Cl<sup>−</sup> permeability of the channel during development. The unedited receptor is activated faster and deactivates slower than the edited receptor.<ref name="pmid17369310"/>
While the effect of editing on protein function is unknown, the developmental increase in editing does correspond to changes in function of the GAGA<sub>A</sub> receptor. GABA binding leads to chloride channel activation, resulting in rapid increase in concentration of the ion. Initially, the receptor is an excitatory receptor, mediating depolarisation (efflux of Cl<sup>−</sup> ions) in immature neurons before changing to an inhibitory receptor, mediating hyperpolarisation(influx of Cl<sup>−</sup> ions) later on.<ref name="pmid12209121">{{cite journal | vauthors = Ben-Ari Y | title = Excitatory actions of gaba during development: the nature of the nurture | journal = Nature Reviews. Neuroscience | volume = 3 | issue = 9 | pages = 728–39 | date = September 2002 | pmid = 12209121 | doi = 10.1038/nrn920 }}</ref> GABA<sub>A</sub> converts to an inhibitory receptor from an excitatory receptor by the upregulation of [[SLC12A5|KCC2]] cotransporter. This decreases the concentration of Cl<sup>−</sup> ion within cells. Therefore, the GAGA<sub>A</sub> subunits are involved in determining the nature of the receptor in response to GABA ligand.<ref name="pmid15199051">{{cite journal | vauthors = Böhme I, Rabe H, Lüddens H | title = Four amino acids in the alpha subunits determine the gamma-aminobutyric acid sensitivities of GABAA receptor subtypes | journal = The Journal of Biological Chemistry | volume = 279 | issue = 34 | pages = 35193–200 | date = August 2004 | pmid = 15199051 | doi = 10.1074/jbc.M405653200 }}</ref> These changes suggest that editing of the subunit is important in the developing brain by regulating the Cl<sup>−</sup> permeability of the channel during development. The unedited receptor is activated faster and deactivates slower than the edited receptor.<ref name="pmid17369310"/>


==See also==
== See also ==
* [[GABAA receptor|GABA<sub>A</sub> receptor]]
* [[GABAA receptor|GABA<sub>A</sub> receptor]]


==References==
== References ==
{{Reflist}}
{{Reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
*{{cite journal |vauthors=Buckle VJ, Fujita N, Ryder-Cook AS |title=Chromosomal localization of GABAA receptor subunit genes: relationship to human genetic disease. |journal=Neuron |volume=3 |issue= 5 |pages= 647–54 |year= 1990 |pmid= 2561974 |doi=10.1016/0896-6273(89)90275-4 |display-authors=etal}}
* {{cite journal | vauthors = Buckle VJ, Fujita N, Ryder-Cook AS, Derry JM, Barnard PJ, Lebo RV, Schofield PR, Seeburg PH, Bateson AN, Darlison MG | title = Chromosomal localization of GABAA receptor subunit genes: relationship to human genetic disease | journal = Neuron | volume = 3 | issue = 5 | pages = 647–54 | date = November 1989 | pmid = 2561974 | doi = 10.1016/0896-6273(89)90275-4 }}
*{{cite journal |vauthors=Bell MV, Bloomfield J, McKinley M |title=Physical linkage of a GABAA receptor subunit gene to the DXS374 locus in human Xq28. |journal=Am. J. Hum. Genet. |volume=45 |issue= 6 |pages= 883–8 |year= 1990 |pmid= 2574000 |doi=  | pmc=1683479 |display-authors=etal}}
* {{cite journal | vauthors = Bell MV, Bloomfield J, McKinley M, Patterson MN, Darlison MG, Barnard EA, Davies KE | title = Physical linkage of a GABAA receptor subunit gene to the DXS374 locus in human Xq28 | journal = American Journal of Human Genetics | volume = 45 | issue = 6 | pages = 883–8 | date = December 1989 | pmid = 2574000 | pmc = 1683479 | doi = }}
*{{cite journal |vauthors=Tögel M, Mossier B, Fuchs K, Sieghart W |title=gamma-Aminobutyric acidA receptors displaying association of gamma 3-subunits with beta 2/3 and different alpha-subunits exhibit unique pharmacological properties. |journal=J. Biol. Chem. |volume=269 |issue= 17 |pages= 12993–8 |year= 1994 |pmid= 8175718 |doi=  }}
* {{cite journal | vauthors = Tögel M, Mossier B, Fuchs K, Sieghart W | title = gamma-Aminobutyric acidA receptors displaying association of gamma 3-subunits with beta 2/3 and different alpha-subunits exhibit unique pharmacological properties | journal = The Journal of Biological Chemistry | volume = 269 | issue = 17 | pages = 12993–8 | date = April 1994 | pmid = 8175718 | doi =  }}
*{{cite journal |vauthors=Hadingham KL, Wingrove P, Le Bourdelles B |title=Cloning of cDNA sequences encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits and characterization of the benzodiazepine pharmacology of recombinant alpha 1-, alpha 2-, alpha 3-, and alpha 5-containing human gamma-aminobutyric acidA receptors. |journal=Mol. Pharmacol. |volume=43 |issue= 6 |pages= 970–5 |year= 1993 |pmid= 8391122 |doi=  |display-authors=etal}}
* {{cite journal | vauthors = Hadingham KL, Wingrove P, Le Bourdelles B, Palmer KJ, Ragan CI, Whiting PJ | title = Cloning of cDNA sequences encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits and characterization of the benzodiazepine pharmacology of recombinant alpha 1-, alpha 2-, alpha 3-, and alpha 5-containing human gamma-aminobutyric acidA receptors | journal = Molecular Pharmacology | volume = 43 | issue = 6 | pages = 970–5 | date = June 1993 | pmid = 8391122 | doi =  }}
*{{cite journal |vauthors=Belelli D, Lambert JJ, Peters JA |title=The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 20 |pages= 11031–6 |year= 1997 |pmid= 9380754 |doi=10.1073/pnas.94.20.11031 | pmc=23576  |display-authors=etal}}
* {{cite journal | vauthors = Belelli D, Lambert JJ, Peters JA, Wafford K, Whiting PJ | title = The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 20 | pages = 11031–6 | date = September 1997 | pmid = 9380754 | pmc = 23576 | doi = 10.1073/pnas.94.20.11031 }}
*{{cite journal |vauthors=Huang RQ, Dillon GH |title=Maintenance of recombinant type A gamma-aminobutyric acid receptor function: role of protein tyrosine phosphorylation and calcineurin. |journal=J. Pharmacol. Exp. Ther. |volume=286 |issue= 1 |pages= 243–55 |year= 1998 |pmid= 9655866 |doi=  }}
* {{cite journal | vauthors = Huang RQ, Dillon GH | title = Maintenance of recombinant type A gamma-aminobutyric acid receptor function: role of protein tyrosine phosphorylation and calcineurin | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 286 | issue = 1 | pages = 243–55 | date = July 1998 | pmid = 9655866 | doi =  }}
*{{cite journal |vauthors=Amir R, Dahle EJ, Toriolo D, Zoghbi HY |title=Candidate gene analysis in Rett syndrome and the identification of 21 SNPs in Xq. |journal=Am. J. Med. Genet. |volume=90 |issue= 1 |pages= 69–71 |year= 2000 |pmid= 10602120 |doi=10.1002/(SICI)1096-8628(20000103)90:1<69::AID-AJMG12>3.0.CO;2-W }}
* {{cite journal | vauthors = Amir R, Dahle EJ, Toriolo D, Zoghbi HY | title = Candidate gene analysis in Rett syndrome and the identification of 21 SNPs in Xq | journal = American Journal of Medical Genetics | volume = 90 | issue = 1 | pages = 69–71 | date = January 2000 | pmid = 10602120 | doi = 10.1002/(SICI)1096-8628(20000103)90:1<69::AID-AJMG12>3.0.CO;2-W }}
*{{cite journal |vauthors=Bedford FK, Kittler JT, Muller E |title=GABA(A) receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1. |journal=Nat. Neurosci. |volume=4 |issue= 9 |pages= 908–16 |year= 2001 |pmid= 11528422 |doi= 10.1038/nn0901-908 |display-authors=etal}}
* {{cite journal | vauthors = Bedford FK, Kittler JT, Muller E, Thomas P, Uren JM, Merlo D, Wisden W, Triller A, Smart TG, Moss SJ | title = GABA(A) receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1 | journal = Nature Neuroscience | volume = 4 | issue = 9 | pages = 908–16 | date = September 2001 | pmid = 11528422 | doi = 10.1038/nn0901-908 }}
*{{cite journal |vauthors=Strausberg RL, Feingold EA, Grouse LH |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241 |display-authors=etal}}
* {{cite journal | vauthors = Chou KC | title = Modelling extracellular domains of GABA-A receptors: subtypes 1, 2, 3, and 5 | journal = Biochemical and Biophysical Research Communications | volume = 316 | issue = 3 | pages = 636–42 | date = April 2004 | pmid = 15033447 | doi = 10.1016/j.bbrc.2004.02.098 }}
*{{cite journal  | author=Chou KC |title=Modelling extracellular domains of GABA-A receptors: subtypes 1, 2, 3, and 5. |journal=Biochem. Biophys. Res. Commun. |volume=316 |issue= 3 |pages= 636–42 |year= 2004 |pmid= 15033447 |doi= 10.1016/j.bbrc.2004.02.098 }}
* {{cite journal | vauthors = Henkel V, Baghai TC, Eser D, Zill P, Mergl R, Zwanzger P, Schüle C, Bottlender R, Jäger M, Rupprecht R, Hegerl U, Möller HJ, Bondy B | title = The gamma amino butyric acid (GABA) receptor alpha-3 subunit gene polymorphism in unipolar depressive disorder: a genetic association study | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 126B | issue = 1 | pages = 82–7 | date = April 2004 | pmid = 15048654 | doi = 10.1002/ajmg.b.20137 }}
*{{cite journal |vauthors=Henkel V, Baghai TC, Eser D |title=The gamma amino butyric acid (GABA) receptor alpha-3 subunit gene polymorphism in unipolar depressive disorder: a genetic association study. |journal=Am. J. Med. Genet. B Neuropsychiatr. Genet. |volume=126 |issue= 1 |pages= 82–7 |year= 2004 |pmid= 15048654 |doi= 10.1002/ajmg.b.20137 |display-authors=etal}}
* {{cite journal | vauthors = Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S | title = Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes | journal = Genome Research | volume = 16 | issue = 1 | pages = 55–65 | date = January 2006 | pmid = 16344560 | pmc = 1356129 | doi = 10.1101/gr.4039406 }}
*{{cite journal |vauthors=Gerhard DS, Wagner L, Feingold EA |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504  | pmc=528928 |display-authors=etal}}
* {{cite journal | vauthors = Pedersen JS, Bejerano G, Siepel A, Rosenbloom K, Lindblad-Toh K, Lander ES, Kent J, Miller W, Haussler D | title = Identification and classification of conserved RNA secondary structures in the human genome | journal = PLoS Computational Biology | volume = 2 | issue = 4 | pages = e33 | date = April 2006 | pmid = 16628248 | pmc = 1440920 | doi = 10.1371/journal.pcbi.0020033 }}
*{{cite journal  |vauthors=Kimura K, Wakamatsu A, Suzuki Y |title=Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. |journal=Genome Res. |volume=16 |issue= 1 |pages= 55–65 |year= 2006 |pmid= 16344560 |doi= 10.1101/gr.4039406 | pmc=1356129 |display-authors=etal}}
*{{cite journal |vauthors=Pedersen JS, Bejerano G, Siepel A |title=Identification and classification of conserved RNA secondary structures in the human genome |journal=PLoS Comput. Biol. |volume=2 |issue=4 |pages=e33 |date=April 2006 |pmid=16628248 |pmc=1440920 |doi=10.1371/journal.pcbi.0020033 |url=http://dx.plos.org/10.1371/journal.pcbi.0020033 |accessdate=2010-07-19|display-authors=etal}}
{{refend}}
{{refend}}


Latest revision as of 22:44, 5 September 2018

VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

n/a

n/a

Ensembl

n/a

n/a

UniProt

n/a

n/a

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Gamma-aminobutyric acid receptor subunit alpha-3 is a protein that in humans is encoded by the GABRA3 gene.[1]

Function

GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABAA receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABAA receptor. At least 16 distinct subunits of GABA-A receptors have been identified.[1] GABA receptors are composed of 5 subunits with an extracellular ligand binding domains and ion channel domains that are integral to the membrane.Ligand binding to these receptors activates the channel.[2]

Subunit selective ligands

Recent research has produced several ligands that are selective for GABAA receptors containing the α3 subunit. Subtype-selective agonists for α3 produce anxiolytic effects without sedative, amnesia, ataxia. [3] selective a3 agonists also show lack of dependence, [4] and could make them superior to currently marketed drugs.

Agonists

  • Adipiplon
  • PWZ-029 (partial agonist at α3, partial inverse agonist at α5)
  • TP003 (Selective full agonist at α3)

Inverse agonists

  • α3IA

RNA editing

Editing element of GABA-3 exon 9
File:GABRA3RNA.png
Identifiers
SymbolGABA3
RfamRF01803
Other data
RNA typeCis-reg;
Domain(s)Eukaryota;
SO0005836
PDB structuresPDBe

The GABRA3 transcript undergoes pre-mRNA editing by the ADAR family of enzymes.[5] A-to-I editing changes an isoleucine codon to code for a methionine residue. This editing is thought to be important for brain development, as the level of editing is low at birth and becomes almost 100% in an adult brain.[5]

The editing occurs in an RNA stem-loop found in exon 9.[5] The structured loci was identified using a specialised bioinformatics screen[6] of the human genome. The proposed function of the edit is to alter chloride permeability of the GABA receptor.[5]

At the time of discovery, Kv1.1 mRNA was the only previously known mammalian coding site containing both the edit sequence and the editing complementary sequence.[7]

Type

A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR 2 are widely expressed in tissues, while ADAR3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site, with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS).

Location

The editing site was previously believed to be a single nucleotide polymorphism.[8] The editing site is found at amino acid 5 of transmembrane domain 3 of exon 9. The predicted double-stranded RNA structure is interrupted by three bulges and a mismatch at the editing site. The double-stranded region is 22 base pairs in length. As with editing of the KCNA1 gene product,[7] the editing region and the editing complementary sequence are both found in exonic regions. In the pre=mRNA of GABRA3, both are found within exon 9.[5] The other subunits of the receptor are thought not to be edited, as their predicted secondary structure is less likely to be edited. Also, alpha subunits 1 and 6 have a uridine instead of an adenosine at the site corresponding to the editing site in alpha subunit 3.[5] Point mutation experiments determined that a Cytidine 15 nucleotides from the editing site is the base opposite the edited base.[5] Using a GABRA3 mini-gene that encodes for exon 9 cotransfected to HEK293 cells with either ADAR1 or -2 or none, it was determined that both active ADARs can efficiently edited the site in exon 9.[5]

Regulation

The mRNA expression of the alpha 3 subunit is developmentally regulated. It is the dominant subunit in the forebrain tissue at birth, gradually decreasing in prominence as alpha subunit 1 takes over. Also experiments with mice have demonstrated that editing of pre-mRNA alpha 3 subunit increases from 50% at birth to nearly 100% in adult.[5] Editing levels are lower in the hippocampus[9]

Conservation

At the location corresponding to the I/M site of GABRA3 in frog and pufferfish there is a genomically encoded methionine. In all other species, there is an isoleucine at the position.[10]

Consequences

Structure

Editing results in a codon change from (AUA)I to (AUG)M at the editing site. This results in translation of a methionine instead of an isoleucine at the I/M site. The amino acid change occurs in the transmembrane domain 3. The 4 transmembrane domains of each of the 5 subunits that make up the receptor interact to form the receptor channel. It is likely that the change of amino acids disturbs the structure, effecting gating and inactivation of the channel.[11] This is because methionine has a larger side chain.[5]

Function

While the effect of editing on protein function is unknown, the developmental increase in editing does correspond to changes in function of the GAGAA receptor. GABA binding leads to chloride channel activation, resulting in rapid increase in concentration of the ion. Initially, the receptor is an excitatory receptor, mediating depolarisation (efflux of Cl− ions) in immature neurons before changing to an inhibitory receptor, mediating hyperpolarisation(influx of Cl− ions) later on.[12] GABAA converts to an inhibitory receptor from an excitatory receptor by the upregulation of KCC2 cotransporter. This decreases the concentration of Cl− ion within cells. Therefore, the GAGAA subunits are involved in determining the nature of the receptor in response to GABA ligand.[13] These changes suggest that editing of the subunit is important in the developing brain by regulating the Cl− permeability of the channel during development. The unedited receptor is activated faster and deactivates slower than the edited receptor.[5]

See also

References

  1. ↑ 1.0 1.1 "Entrez Gene: GABRA3 gamma-aminobutyric acid (GABA) A receptor, alpha 3".
  2. ↑ Cromer BA, Morton CJ, Parker MW (June 2002). "Anxiety over GABA(A) receptor structure relieved by AChBP". Trends in Biochemical Sciences. 27 (6): 280–7. doi:10.1016/S0968-0004(02)02092-3. PMID 12069787.
  3. ↑ Fischer BD, Atack JR, Platt DM, et al. (2011). "Contribution of GABAA receptors containing α3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys". Psychopharmacology. 215 (2): 311–319. doi:10.1007/s00213-010-2142-y. PMC 3097109. PMID 21190016.
  4. ↑ Cheng T, Wallace D, Ponteri B, et al. (2018). "Valium without dependence? Individual GABAA receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects". Neuropsychiatr. Dis. Treat. 14: 1351–1361. doi:10.2147/NDT.S164307. PMC 5973310. PMID 29872302.
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 Ohlson J, Pedersen JS, Haussler D, Ohman M (May 2007). "Editing modifies the GABA(A) receptor subunit alpha3". RNA. 13 (5): 698–703. doi:10.1261/rna.349107. PMC 1852825. PMID 17369310.
  6. ↑ Ohlson J, Ensterö M, Sjöberg BM, Ohman M (October 2005). "A method to find tissue-specific novel sites of selective adenosine deamination". Nucleic Acids Research. 33 (19): e167. doi:10.1093/nar/gni169. PMC 1275595. PMID 16257978.
  7. ↑ 7.0 7.1 Bhalla T, Rosenthal JJ, Holmgren M, Reenan R (October 2004). "Control of human potassium channel inactivation by editing of a small mRNA hairpin". Nature Structural & Molecular Biology. 11 (10): 950–6. doi:10.1038/nsmb825. PMID 15361858.
  8. ↑ Wang Q, Miyakoda M, Yang W, Khillan J, Stachura DL, Weiss MJ, Nishikura K (February 2004). "Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene". The Journal of Biological Chemistry. 279 (6): 4952–61. doi:10.1074/jbc.M310162200. PMID 14613934.
  9. ↑ Rula EY, Lagrange AH, Jacobs MM, Hu N, Macdonald RL, Emeson RB (June 2008). "Developmental modulation of GABA(A) receptor function by RNA editing". The Journal of Neuroscience. 28 (24): 6196–201. doi:10.1523/JNEUROSCI.0443-08.2008. PMC 2746000. PMID 18550761.
  10. ↑ Hinrichs AS, Karolchik D, Baertsch R, Barber GP, Bejerano G, Clawson H, Diekhans M, Furey TS, Harte RA, Hsu F, Hillman-Jackson J, Kuhn RM, Pedersen JS, Pohl A, Raney BJ, Rosenbloom KR, Siepel A, Smith KE, Sugnet CW, Sultan-Qurraie A, Thomas DJ, Trumbower H, Weber RJ, Weirauch M, Zweig AS, Haussler D, Kent WJ (January 2006). "The UCSC Genome Browser Database: update 2006". Nucleic Acids Research. 34 (Database issue): D590–8. doi:10.1093/nar/gkj144. PMC 1347506. PMID 16381938.
  11. ↑ Fisher JL (April 2004). "A mutation in the GABAA receptor alpha 1 subunit linked to human epilepsy affects channel gating properties". Neuropharmacology. 46 (5): 629–37. doi:10.1016/j.neuropharm.2003.11.015. PMID 14996540.
  12. ↑ Ben-Ari Y (September 2002). "Excitatory actions of gaba during development: the nature of the nurture". Nature Reviews. Neuroscience. 3 (9): 728–39. doi:10.1038/nrn920. PMID 12209121.
  13. ↑ Böhme I, Rabe H, Lüddens H (August 2004). "Four amino acids in the alpha subunits determine the gamma-aminobutyric acid sensitivities of GABAA receptor subtypes". The Journal of Biological Chemistry. 279 (34): 35193–200. doi:10.1074/jbc.M405653200. PMID 15199051.

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

Retrieved from "https://www.wikidoc.org/index.php?title=GABRA3&oldid=1534215"