Glutamate decarboxylase: Difference between revisions

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{{protein
{{enzyme
| Name = glutamate decarboxylase
| EC_number = 4.1.1.15
| CAS_number = 9024-58-2m
| IUBMB_EC_number = 4/1/1/15
| GO_code = 0004351
| image =
| width =
| caption =
}}
{{infobox protein
| Name = [[GAD1|Glutamic acid decarboxylase 1]]
| Name = [[GAD1|Glutamic acid decarboxylase 1]]
| caption =  
| caption = GAD67 derived from {{PDB|2okj}}
| image =  
| image = PDB GAD67.jpg
| width =  
| width =  
| HGNCid = 4092
| HGNCid = 4092
| Symbol = [[GAD1]]
| Symbol = [[GAD1]]
| AltSymbols = GLUTAMATE DECARBOXYLASE, BRAIN, 67-KD; GAD67
| AltSymbols = glutamate decarboxylase 1<br />(brain, 67kD); GAD67
| EntrezGene = 2571
| EntrezGene = 2571
| OMIM = 605363
| OMIM = 605363
| RefSeq =
| RefSeq = NM_000817
| UniProt = Q99259
| UniProt = Q99259
| PDB =  
| PDB =  
Line 18: Line 28:
| LocusSupplementaryData =  
| LocusSupplementaryData =  
}}
}}
{{protein
{{infobox protein
| Name = [[GAD2|glutamic acid decarboxylase 2]]
| Name = [[GAD2|glutamic acid decarboxylase 2]]
| caption =  
| caption =  
Line 25: Line 35:
| HGNCid = 11284
| HGNCid = 11284
| Symbol = [[GAD2]]
| Symbol = [[GAD2]]
| AltSymbols =  
| AltSymbols = GAD65
| EntrezGene = 2572
| EntrezGene = 2572
| OMIM = 4093
| OMIM = 4093
| RefSeq =
| RefSeq = NM_001047
| UniProt = Q05329
| UniProt = Q05329
| PDB = 1ES0
| PDB =
| ECnumber = 4.1.1.15
| ECnumber = 4.1.1.15
| Chromosome = 10
| Chromosome = 10
Line 37: Line 47:
| LocusSupplementaryData =  
| LocusSupplementaryData =  
}}
}}
'''Glutamate decarboxylase''' or '''glutamic acid decarboxylase''' ('''GAD''') is an [[enzyme]] that catalyzes the decarboxylation of [[glutamate]] to [[GABA]] and CO<sub >2</sub>. GAD uses [[Pyridoxal-phosphate|PLP]] as a [[cofactor (biochemistry)|cofactor]]. The reaction proceeds as follows:
: HOOC-CH<sub >2</sub>-CH<sub >2</sub>-CH(NH<sub >2</sub>)-COOH → CO<sub >2</sub> + HOOC-CH<sub >2</sub>-CH<sub >2</sub>-CH<sub >2</sub>NH<sub >2</sub>
In mammals, GAD exists in two [[isoform]]s encoded by two different [[gene]]s - [[GAD1]] and [[GAD2]]. These isoforms are GAD<sub>67</sub> and GAD<sub>65</sub> with molecular weights of 67 and 65 [[kDa]], respectively.<ref name="pmid2069816">{{cite journal | vauthors = Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ | title = Two genes encode distinct glutamate decarboxylases | journal = Neuron | volume = 7 | issue = 1 | pages = 91–100 | date = July 1991 | pmid = 2069816 | doi = 10.1016/0896-6273(91)90077-D }}</ref> GAD1 and GAD2 are expressed in the brain where GABA is used as a [[neurotransmitter]], GAD2 is also expressed in the pancreas.
At least two more forms, GAD<sub>25</sub> and GAD<sub>44</sub> (embryonic; EGAD) are described in the developing brain. They are coded by the alternative transcripts of GAD1, I-80 and I-86: GAD<sub>25</sub> is coded by both, GAD<sub>44</sub> - only by I-80.<ref name="pmid7935469">{{cite journal | vauthors = Szabo G, Katarova Z, Greenspan R | title = Distinct protein forms are produced from alternatively spliced bicistronic glutamic acid decarboxylase mRNAs during development | journal = Molecular and Cellular Biology | volume = 14 | issue = 11 | pages = 7535–45 | date = November 1994 | pmid = 7935469 | pmc = 359290 | doi =  10.1128/mcb.14.11.7535}}</ref>
==Regulation of GAD65 and GAD67==
GAD<sub>65</sub> and GAD<sub>67</sub> synthesize GABA at different locations in the cell, at different developmental times, and for functionally different purposes.<ref name="pmid9777629">{{cite journal | vauthors = Pinal CS, Tobin AJ | title = Uniqueness and redundancy in GABA production | journal = Perspectives on Developmental Neurobiology | volume = 5 | issue = 2–3 | pages = 109–18 | year = 1998 | pmid = 9777629 }}</ref> GAD<sub>67</sub> is spread evenly throughout the cell while GAD<sub>65</sub> is localized to nerve terminals.<ref name="pmid9777629"/> This difference is thought to reflect a functional difference; GAD<sub>67</sub> synthesizes GABA for neuron activity unrelated to neurotransmission, such as synaptogenesis and protection from neural injury.<ref name="pmid9777629"/> This function requires widespread, ubiquitous presence of GABA. GAD<sub>65</sub>, however, synthesizes GABA for neurotransmission,<ref name="pmid9777629"/> and therefore is only necessary at nerve terminals and synapses. In order to aid in neurotransmission, GAD<sub>65</sub> forms a complex with Heat Shock Cognate 70 (HSC<sub>70</sub>), cysteine string protein (CSP) and Vesicular GABA transporter VGAT, which, as a complex, helps package GABA into vesicles for release during neurotransmission.<ref>{{cite journal | vauthors = Jin H, Wu H, Osterhaus G, Wei J, Davis K, Sha D, Floor E, Hsu CC, Kopke RD, Wu JY | title = Demonstration of functional coupling between gamma -aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 7 | pages = 4293–8 | date = April 2003 | pmid = 12634427 | pmc = 153086 | doi = 10.1073/pnas.0730698100 }}</ref> GAD<sub>67</sub> is transcribed during early development, while GAD<sub>65</sub> is not transcribed until later in life.<ref name="pmid9777629"/> This developmental difference in GAD<sub>67</sub> and GAD<sub>65</sub> reflects the functional properties of each isoform; GAD<sub>67</sub> is needed throughout development for normal cellular functioning, while GAD<sub>65</sub> is not needed until slightly later in development when synaptic inhibition is more prevalent.<ref name="pmid9777629"/>
GAD<sub>67</sub> and GAD<sub>65</sub> are also regulated differently post-translationally. Both GAD<sub>65</sub> and GAD<sub>67</sub> are regulated via phosphorylation,<ref>{{cite journal | vauthors = Wei J, Davis KM, Wu H, Wu JY | title = Protein phosphorylation of human brain glutamic acid decarboxylase (GAD)65 and GAD67 and its physiological implications | journal = Biochemistry | volume = 43 | issue = 20 | pages = 6182–9 | date = May 2004 | pmid = 15147202 | pmc =  | doi = 10.1021/bi0496992 }}</ref> but the regulation of these isoforms differs; GAD<sub>65</sub> is activated by phosphorylation while GAD<sub>67</sub> is inhibited by phosphorylation. GAD<sub>67</sub> is phosphorylated at threonine 91 by protein kinase A (PKA), while GAD<sub>65</sub> is phosphorylated, and therefore regulated by, protein kinase C (PKC). Both GAD<sub>67</sub> and GAD<sub>65</sub> are also regulated post-translationally by [[Pyridoxal phosphate|Pyridoxal 5’-phosphate]] (PLP); GAD is activated when bound to PLP and inactive when not bound to PLP.<ref name="pmid12887686">{{cite journal | vauthors = Battaglioli G, Liu H, Martin DL | title = Kinetic differences between the isoforms of glutamate decarboxylase: implications for the regulation of GABA synthesis | journal = Journal of Neurochemistry | volume = 86 | issue = 4 | pages = 879–87 | date = August 2003 | pmid = 12887686 | doi = 10.1046/j.1471-4159.2003.01910.x }}</ref> Majority of GAD<sub>67</sub> is bound to PLP at any given time, whereas GAD<sub>65</sub> binds PLP when GABA is needed for neurotransmission.<ref name="pmid12887686"/> This reflects the functional properties of the two isoforms; GAD<sub>67</sub> must be active at all times for normal cellular functioning, and is therefore constantly activated by PLP, while GAD<sub>65</sub> must only be activated when GABA neurotransmission occurs, and is therefore regulated according to the synaptic environment.
== Role in pathology ==
=== Diabetes ===
Both GAD<sub>67</sub> and GAD<sub>65</sub> are targets of [[autoantibody|autoantibodies]] in people who later develop type 1 [[diabetes mellitus]] or [[latent autoimmune diabetes]].<ref name="pmid1697648">{{cite journal | vauthors = Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, De Camilli P, Camilli PD | title = Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase | journal = Nature | volume = 347 | issue = 6289 | pages = 151–6 | date = September 1990 | pmid = 1697648 | doi = 10.1038/347151a0 }}</ref><ref name="pmid1370298">{{cite journal | vauthors = Kaufman DL, Erlander MG, Clare-Salzler M, Atkinson MA, Maclaren NK, Tobin AJ | title = Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus | journal = The Journal of Clinical Investigation | volume = 89 | issue = 1 | pages = 283–92 | date = January 1992 | pmid = 1370298 | pmc = 442846 | doi = 10.1172/JCI115573 }}</ref> Injections with GAD<sub>65</sub> has been shown to preserve some insulin production for 30 months in humans with type 1 diabetes.<ref name="pmid18843118">{{cite journal | vauthors = Ludvigsson J, Faresjö M, Hjorth M, Axelsson S, Chéramy M, Pihl M, Vaarala O, Forsander G, Ivarsson S, Johansson C, Lindh A, Nilsson NO, Aman J, Ortqvist E, Zerhouni P, Casas R | title = GAD treatment and insulin secretion in recent-onset type 1 diabetes | journal = The New England Journal of Medicine | volume = 359 | issue = 18 | pages = 1909–20 | date = October 2008 | pmid = 18843118 | doi = 10.1056/NEJMoa0804328 }}</ref><ref name="url_Diamyd">{{cite web | url = http://www.diamyd.com/docs/pressClip.aspx?section=investor&ClipID=420 | title = Diamyd announces completion of type 1 diabetes vaccine trial with long term efficacy demonstrated at 30 months | author = | date = 2008-01-28 | work = Press Release | publisher = Diamyd Medical AB | pages = | accessdate = 2010-01-13 }}</ref>
===Stiff Person Syndrome===


{{SI}}
High [[titer]]s of autoantibodies to glutamic acid decarboxylase (GAD) are well documented in association with [[stiff person syndrome]] (SPS). Glutamic acid decarboxylase is the rate-limiting enzyme in the synthesis of γ-aminobutyric acid (GABA), and impaired function of GABAergic neurons has been implicated in the pathogenesis of SPS. Autoantibodies to GAD might be the causative agent or a disease marker.<ref>{{cite journal | vauthors = Chang T, Alexopoulos H, McMenamin M, Carvajal-González A, Alexander SK, Deacon R, Erdelyi F, Szabó G, Gabor S, Lang B, Blaes F, Brown P, Vincent A | title = Neuronal surface and glutamic acid decarboxylase autoantibodies in Nonparaneoplastic stiff person syndrome | journal = JAMA Neurology | volume = 70 | issue = 9 | pages = 1140–9 | date = September 2013 | pmid = 23877118 | doi = 10.1001/jamaneurol.2013.3499 }}</ref>


=== Schizophrenia and bipolar disorder ===


==Overview==
Substantial dysregulation of GAD mRNA expression, coupled with downregulation of [[reelin]], is observed in [[schizophrenia]] and [[bipolar disorder]].<ref name="pmid15237077">{{cite journal | vauthors = Woo TU, Walsh JP, Benes FM | title = Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder | journal = Archives of General Psychiatry | volume = 61 | issue = 7 | pages = 649–57 | date = July 2004 | pmid = 15237077 | doi = 10.1001/archpsyc.61.7.649 }}</ref> The most pronounced downregulation of GAD<sub>67</sub> was found in hippocampal [[stratum oriens]] layer in both disorders and in other layers and structures of hippocampus with varying degrees.<ref name="pmid17553960">{{cite journal | vauthors = Benes FM, Lim B, Matzilevich D, Walsh JP, Subburaju S, Minns M | title = Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 24 | pages = 10164–9 | date = June 2007 | pmid = 17553960 | pmc = 1888575 | doi = 10.1073/pnas.0703806104 }}</ref>
'''Glutamate decarboxylase''' (GAD) is an [[enzyme]] that catalyzes the decarboxylation of [[glutamate]] to [[GABA]] and CO<sub >2</sub >. GAD uses [[Pyridoxal-phosphate|PLP]] as a [[cofactor]]. The reaction proceeds as follows:


HOOC-CH<sub >2</sub >-CH<sub >2</sub >-CH(NH<sub >2</sub >)-COOH → CO<sub >2</sub > + HOOC-CH<sub >2</sub >-CH<sub >2</sub >-CH<sub >2</sub >NH<sub >2</sub >
GAD<sub>67</sub> is a key enzyme involved in the synthesis of inhibitory neurotransmitter [[GABA]] and people with schizophrenia have been shown to express lower amounts of GAD<sub>67</sub> in the dorsolateral prefrontal cortex compared to healthy controls.<ref name="pmid24874453">{{cite journal | vauthors = Kimoto S, Bazmi HH, Lewis DA | title = Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex in schizophrenia: contribution of altered regulation by Zif268 | journal = The American Journal of Psychiatry | volume = 171 | issue = 9 | pages = 969–78 | date = September 2014 | pmid = 24874453 | doi = 10.1176/appi.ajp.2014.14010004 | pmc=4376371}}</ref> The mechanism underlying the decreased levels of GAD<sub>67</sub> in people with schizophrenia remains unclear.  Some have proposed that an immediate early gene, Zif268, which normally binds to the [[promoter (genetics)|promoter]] region of GAD<sub>67</sub> and increases transcription of GAD<sub>67</sub>, is lower in schizophrenic patients, thus contributing to decreased levels of GAD<sub>67</sub>.<ref name="pmid24874453"/>  Since the dorsolateral prefrontal cortex (DLPFC) is involved in working memory, and GAD<sub>67</sub> and Zif268 mRNA levels are lower in the DLPFC of schizophrenic patients, this molecular alteration may account, at least in part, for the working memory impairments associated with the disease.


In mammals, GAD exists in two [[isoform]]s encoded by two different [[gene]]s - ''Gad1'' and ''Gad2''. These isoforms are GAD<sub>67</sub> and GAD<sub>65</sub> with molecular weights of 67 and 65 [[kDa]], respectively.<ref name="pmid2069816">{{cite journal | author = Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ | title = Two genes encode distinct glutamate decarboxylases | journal = Neuron | volume = 7 | issue = 1 | pages = 91–100 | year = 1991 | pmid = 2069816 | doi = 10.1016/0896-6273(91)90077-D | issn = }}</ref> GAD1 and GAD2 are expressed in the brain where GABA is used as a [[neurotransmitter]], GAD2 is also expressed in the pancreas.
=== Parkinson disease ===


==Role in pathology==
The bilateral delivery of [[glutamic acid decarboxylase]] (GAD) by an [[adeno-associated viral vector]] into the subthalamic nucleus of patients between 30 and 75 years of age with advanced, progressive, levodopa-responsive [[Parkinson disease]] resulted in significant improvement over baseline during the course of a six-month study.<ref name="pmid21419704">{{cite journal | vauthors = LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, Kostyk SK, Thomas K, Sarkar A, Siddiqui MS, Tatter SB, Schwalb JM, Poston KL, Henderson JM, Kurlan RM, Richard IH, Van Meter L, Sapan CV, During MJ, Kaplitt MG, Feigin A | title = AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial | journal = The Lancet. Neurology | volume = 10 | issue = 4 | pages = 309–19 | date = April 2011 | pmid = 21419704 | doi = 10.1016/S1474-4422(11)70039-4 }}</ref>


===Diabetes===
=== Cerebellar disorders ===
Both GAD<sub>67</sub> and GAD<sub>65</sub> are targets of autoantibodies in people who later develop insulin-dependent [[diabetes mellitus]].<ref name="pmid1697648">{{cite journal | author = Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, De Camilli P, Camilli PD | title = Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase | journal = Nature | volume = 347 | issue = 6289 | pages = 151–6 | year = 1990 | pmid = 1697648 | doi = 10.1038/347151a0 | issn = }}</ref> <ref name="pmid1370298">{{cite journal | author = Kaufman DL, Erlander MG, Clare-Salzler M, Atkinson MA, Maclaren NK, Tobin AJ | title = Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus | journal = J. Clin. Invest. | volume = 89 | issue = 1 | pages = 283–92 | year = 1992 | pmid = 1370298 | doi = | issn = | url = http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=1370298}}</ref> Injections with GAD<sub>65</sub> has been shown to preserve some insulin production for 30 months in humans with type 1 diabetes.<ref>[http://www.diamyd.se/docs/PressClip.aspx?PageID=4&LangID=2&ClipID=420&sm=b_b Diamyd press release]</ref>


===Schizophrenia and Bipolar disorder===
Intracerebellar administration of GAD autoantibodies to animals increases the excitability of motoneurons and impairs the production of [[Biological functions of nitric oxide|nitric oxide]] (NO), a molecule involved in learning. Epitope recognition contributes to cerebellar involvement.<ref>{{cite journal | vauthors = Manto MU, Hampe CS, Rogemond V, Honnorat J | title = Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia | journal = Orphanet Journal of Rare Diseases | volume = 6 | issue = 3 | pages = 3 | date = February 2011 | pmid = 21294897 | doi = 10.1186/1750-1172-6-3 | pmc=3042903}}</ref> Reduced GABA levels increase glutamate levels as a consequence of lower inhibition of  subtypes of GABA receptors. Higher glutamate levels activate microglia and activation of xc(−) increases the extracellular glutamate release.<ref>{{Cite journal|last=Mitoma|first=Hiroshi|last2=Manto|first2=Mario|last3=Hampe|first3=Christiane S.|date=2017-03-12|title=Pathogenic Roles of Glutamic Acid Decarboxylase 65 Autoantibodies in Cerebellar Ataxias|url=https://doi.org/10.1155/2017/2913297|journal=Journal of Immunology Research|language=en|volume=2017|pages=1–12|doi=10.1155/2017/2913297|issn=2314-8861}}</ref>
Substantial dysregulation of GAD mRNA expression, coupled with downregulation of [[reelin]], is observed in [[schizophrenia]] and [[bipolar disorder]].<ref name="pmid15237077">{{cite journal | author = Woo TU, Walsh JP, Benes FM | title = Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder | journal = Arch. Gen. Psychiatry | volume = 61 | issue = 7 | pages = 649–57 | year = 2004 | pmid = 15237077 | doi = 10.1001/archpsyc.61.7.649 | issn = }}</ref> The most pronounced downregulation of GAD67 was found in hippocampal [[stratum oriens]] layer in both disorders and in other layers and structures of hippocampus with varying degrees.<ref name="pmid17553960">{{cite journal | author = Benes FM, Lim B, Matzilevich D, Walsh JP, Subburaju S, Minns M | title = Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 104 | issue = 24 | pages = 10164–9 | year = 2007 | pmid = 17553960 | doi = 10.1073/pnas.0703806104 | issn = }}</ref>
 
=== Neuropathic pain ===
 
[[Peripheral nerve injury]] of the sciatic nerve (a [[neuropathic pain]] model) induces a transient loss of GAD<sub>65</sub> immunoreactive terminals in the [[spinal cord]] [[posterior horn of spinal cord|dorsal horn]] and suggests a potential involvement for these alterations in the development and amelioration of pain behaviour.<ref name="pmid 25189404">{{cite journal | vauthors = Lorenzo LE, Magnussen C, Bailey AL, St Louis M, De Koninck Y, Ribeiro-da-Silva A | title = Spatial and temporal pattern of changes in the number of GAD65-immunoreactive inhibitory terminals in the rat superficial dorsal horn following peripheral nerve injury | journal = Molecular Pain | volume = 10 | issue = 1 | pages = 57 | date = September 2014 | pmid = 25189404 | doi = 10.1186/1744-8069-10-57 | pmc=4164746}}</ref>
 
==Other Anti-GAD-associated neurologic disorders==
 
Antibodies directed against glutamic acid decarboxylase (GAD) are increasingly found in patients with other symptoms indicative of central nervous system (CNS) dysfunction, such as [[ataxia]], progressive encephalomyelitis with rigidity and myoclonus [[(PERM)]], [[limbic encephalitis]], and [[epilepsy]].<ref>{{cite journal | vauthors = Dayalu P, Teener JW | title = Stiff Person syndrome and other anti-GAD-associated neurologic disorders | journal = Seminars in Neurology | volume = 32 | issue = 5 | pages = 544–9 | date = November 2012 | pmid = 23677666 | doi = 10.1055/s-0033-1334477 | ref = PMID 23677666 }}</ref>


== References ==
== References ==
{{Reflist|2}}
{{reflist|33em}}


== External links ==
== External links ==
* [http://www.schizophreniaforum.org/new/detail.asp?id=1358 Genetics, Expression Profiling Support GABA Deficits in Schizophrenia] - Schizophrenia Research Forum, 25 June 2007.
* {{commons-inline|Category:Glutamate decarboxylase|Glutamate decarboxylase}}
* [https://web.archive.org/web/20070815162255/http://www.schizophreniaforum.org/new/detail.asp?id=1358 Genetics, Expression Profiling Support GABA Deficits in Schizophrenia] - Schizophrenia Research Forum, 25 June 2007.
 
{{Neurotransmitter metabolism enzymes}}
{{Carbon-carbon lyases}}
{{Enzymes}}
{{GABA metabolism and transport modulators}}
{{Glutamate metabolism and transport modulators}}
{{Portal bar|Molecular and Cellular Biology|border=no}}


[[Category:EC 4.1.1]]
[[Category:EC 4.1.1]]
[[Category:Molecular neuroscience]]
[[Category:Molecular neuroscience]]
 
[[Category:Biology of bipolar disorder]]
{{Carbon-carbon lyases}}
[[Category:GABA]]
{{Amino acid metabolism enzymes}}
[[Category:Glutamate (neurotransmitter)]]
 
 
[[ru:Глутаматдекарбоксилаза]]
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Revision as of 17:55, 27 October 2017

glutamate decarboxylase
Identifiers
EC number4.1.1.15
CAS number9024-58-2m
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Glutamic acid decarboxylase 1
File:PDB GAD67.jpg
GAD67 derived from PDB: 2okj​
Identifiers
SymbolGAD1
Alt. symbolsglutamate decarboxylase 1
(brain, 67kD); GAD67
Entrez2571
HUGO4092
OMIM605363
RefSeqNM_000817
UniProtQ99259
Other data
EC number4.1.1.15
LocusChr. 2 q31
glutamic acid decarboxylase 2
Identifiers
SymbolGAD2
Alt. symbolsGAD65
Entrez2572
HUGO11284
OMIM4093
RefSeqNM_001047
UniProtQ05329
Other data
EC number4.1.1.15
LocusChr. 10 p11.23

Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO2. GAD uses PLP as a cofactor. The reaction proceeds as follows:

HOOC-CH2-CH2-CH(NH2)-COOH → CO2 + HOOC-CH2-CH2-CH2NH2

In mammals, GAD exists in two isoforms encoded by two different genes - GAD1 and GAD2. These isoforms are GAD67 and GAD65 with molecular weights of 67 and 65 kDa, respectively.[1] GAD1 and GAD2 are expressed in the brain where GABA is used as a neurotransmitter, GAD2 is also expressed in the pancreas.

At least two more forms, GAD25 and GAD44 (embryonic; EGAD) are described in the developing brain. They are coded by the alternative transcripts of GAD1, I-80 and I-86: GAD25 is coded by both, GAD44 - only by I-80.[2]

Regulation of GAD65 and GAD67

GAD65 and GAD67 synthesize GABA at different locations in the cell, at different developmental times, and for functionally different purposes.[3] GAD67 is spread evenly throughout the cell while GAD65 is localized to nerve terminals.[3] This difference is thought to reflect a functional difference; GAD67 synthesizes GABA for neuron activity unrelated to neurotransmission, such as synaptogenesis and protection from neural injury.[3] This function requires widespread, ubiquitous presence of GABA. GAD65, however, synthesizes GABA for neurotransmission,[3] and therefore is only necessary at nerve terminals and synapses. In order to aid in neurotransmission, GAD65 forms a complex with Heat Shock Cognate 70 (HSC70), cysteine string protein (CSP) and Vesicular GABA transporter VGAT, which, as a complex, helps package GABA into vesicles for release during neurotransmission.[4] GAD67 is transcribed during early development, while GAD65 is not transcribed until later in life.[3] This developmental difference in GAD67 and GAD65 reflects the functional properties of each isoform; GAD67 is needed throughout development for normal cellular functioning, while GAD65 is not needed until slightly later in development when synaptic inhibition is more prevalent.[3]

GAD67 and GAD65 are also regulated differently post-translationally. Both GAD65 and GAD67 are regulated via phosphorylation,[5] but the regulation of these isoforms differs; GAD65 is activated by phosphorylation while GAD67 is inhibited by phosphorylation. GAD67 is phosphorylated at threonine 91 by protein kinase A (PKA), while GAD65 is phosphorylated, and therefore regulated by, protein kinase C (PKC). Both GAD67 and GAD65 are also regulated post-translationally by Pyridoxal 5’-phosphate (PLP); GAD is activated when bound to PLP and inactive when not bound to PLP.[6] Majority of GAD67 is bound to PLP at any given time, whereas GAD65 binds PLP when GABA is needed for neurotransmission.[6] This reflects the functional properties of the two isoforms; GAD67 must be active at all times for normal cellular functioning, and is therefore constantly activated by PLP, while GAD65 must only be activated when GABA neurotransmission occurs, and is therefore regulated according to the synaptic environment.

Role in pathology

Diabetes

Both GAD67 and GAD65 are targets of autoantibodies in people who later develop type 1 diabetes mellitus or latent autoimmune diabetes.[7][8] Injections with GAD65 has been shown to preserve some insulin production for 30 months in humans with type 1 diabetes.[9][10]

Stiff Person Syndrome

High titers of autoantibodies to glutamic acid decarboxylase (GAD) are well documented in association with stiff person syndrome (SPS). Glutamic acid decarboxylase is the rate-limiting enzyme in the synthesis of γ-aminobutyric acid (GABA), and impaired function of GABAergic neurons has been implicated in the pathogenesis of SPS. Autoantibodies to GAD might be the causative agent or a disease marker.[11]

Schizophrenia and bipolar disorder

Substantial dysregulation of GAD mRNA expression, coupled with downregulation of reelin, is observed in schizophrenia and bipolar disorder.[12] The most pronounced downregulation of GAD67 was found in hippocampal stratum oriens layer in both disorders and in other layers and structures of hippocampus with varying degrees.[13]

GAD67 is a key enzyme involved in the synthesis of inhibitory neurotransmitter GABA and people with schizophrenia have been shown to express lower amounts of GAD67 in the dorsolateral prefrontal cortex compared to healthy controls.[14] The mechanism underlying the decreased levels of GAD67 in people with schizophrenia remains unclear. Some have proposed that an immediate early gene, Zif268, which normally binds to the promoter region of GAD67 and increases transcription of GAD67, is lower in schizophrenic patients, thus contributing to decreased levels of GAD67.[14] Since the dorsolateral prefrontal cortex (DLPFC) is involved in working memory, and GAD67 and Zif268 mRNA levels are lower in the DLPFC of schizophrenic patients, this molecular alteration may account, at least in part, for the working memory impairments associated with the disease.

Parkinson disease

The bilateral delivery of glutamic acid decarboxylase (GAD) by an adeno-associated viral vector into the subthalamic nucleus of patients between 30 and 75 years of age with advanced, progressive, levodopa-responsive Parkinson disease resulted in significant improvement over baseline during the course of a six-month study.[15]

Cerebellar disorders

Intracerebellar administration of GAD autoantibodies to animals increases the excitability of motoneurons and impairs the production of nitric oxide (NO), a molecule involved in learning. Epitope recognition contributes to cerebellar involvement.[16] Reduced GABA levels increase glutamate levels as a consequence of lower inhibition of subtypes of GABA receptors. Higher glutamate levels activate microglia and activation of xc(−) increases the extracellular glutamate release.[17]

Neuropathic pain

Peripheral nerve injury of the sciatic nerve (a neuropathic pain model) induces a transient loss of GAD65 immunoreactive terminals in the spinal cord dorsal horn and suggests a potential involvement for these alterations in the development and amelioration of pain behaviour.[18]

Other Anti-GAD-associated neurologic disorders

Antibodies directed against glutamic acid decarboxylase (GAD) are increasingly found in patients with other symptoms indicative of central nervous system (CNS) dysfunction, such as ataxia, progressive encephalomyelitis with rigidity and myoclonus (PERM), limbic encephalitis, and epilepsy.[19]

References

  1. ↑ Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ (July 1991). "Two genes encode distinct glutamate decarboxylases". Neuron. 7 (1): 91–100. doi:10.1016/0896-6273(91)90077-D. PMID 2069816.
  2. ↑ Szabo G, Katarova Z, Greenspan R (November 1994). "Distinct protein forms are produced from alternatively spliced bicistronic glutamic acid decarboxylase mRNAs during development". Molecular and Cellular Biology. 14 (11): 7535–45. doi:10.1128/mcb.14.11.7535. PMC 359290. PMID 7935469.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Pinal CS, Tobin AJ (1998). "Uniqueness and redundancy in GABA production". Perspectives on Developmental Neurobiology. 5 (2–3): 109–18. PMID 9777629.
  4. ↑ Jin H, Wu H, Osterhaus G, Wei J, Davis K, Sha D, Floor E, Hsu CC, Kopke RD, Wu JY (April 2003). "Demonstration of functional coupling between gamma -aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles". Proceedings of the National Academy of Sciences of the United States of America. 100 (7): 4293–8. doi:10.1073/pnas.0730698100. PMC 153086. PMID 12634427.
  5. ↑ Wei J, Davis KM, Wu H, Wu JY (May 2004). "Protein phosphorylation of human brain glutamic acid decarboxylase (GAD)65 and GAD67 and its physiological implications". Biochemistry. 43 (20): 6182–9. doi:10.1021/bi0496992. PMID 15147202.
  6. ↑ 6.0 6.1 Battaglioli G, Liu H, Martin DL (August 2003). "Kinetic differences between the isoforms of glutamate decarboxylase: implications for the regulation of GABA synthesis". Journal of Neurochemistry. 86 (4): 879–87. doi:10.1046/j.1471-4159.2003.01910.x. PMID 12887686.
  7. ↑ Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, De Camilli P, Camilli PD (September 1990). "Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase". Nature. 347 (6289): 151–6. doi:10.1038/347151a0. PMID 1697648.
  8. ↑ Kaufman DL, Erlander MG, Clare-Salzler M, Atkinson MA, Maclaren NK, Tobin AJ (January 1992). "Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus". The Journal of Clinical Investigation. 89 (1): 283–92. doi:10.1172/JCI115573. PMC 442846. PMID 1370298.
  9. ↑ Ludvigsson J, Faresjö M, Hjorth M, Axelsson S, Chéramy M, Pihl M, Vaarala O, Forsander G, Ivarsson S, Johansson C, Lindh A, Nilsson NO, Aman J, Ortqvist E, Zerhouni P, Casas R (October 2008). "GAD treatment and insulin secretion in recent-onset type 1 diabetes". The New England Journal of Medicine. 359 (18): 1909–20. doi:10.1056/NEJMoa0804328. PMID 18843118.
  10. ↑ "Diamyd announces completion of type 1 diabetes vaccine trial with long term efficacy demonstrated at 30 months". Press Release. Diamyd Medical AB. 2008-01-28. Retrieved 2010-01-13.
  11. ↑ Chang T, Alexopoulos H, McMenamin M, Carvajal-González A, Alexander SK, Deacon R, Erdelyi F, Szabó G, Gabor S, Lang B, Blaes F, Brown P, Vincent A (September 2013). "Neuronal surface and glutamic acid decarboxylase autoantibodies in Nonparaneoplastic stiff person syndrome". JAMA Neurology. 70 (9): 1140–9. doi:10.1001/jamaneurol.2013.3499. PMID 23877118.
  12. ↑ Woo TU, Walsh JP, Benes FM (July 2004). "Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder". Archives of General Psychiatry. 61 (7): 649–57. doi:10.1001/archpsyc.61.7.649. PMID 15237077.
  13. ↑ Benes FM, Lim B, Matzilevich D, Walsh JP, Subburaju S, Minns M (June 2007). "Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars". Proceedings of the National Academy of Sciences of the United States of America. 104 (24): 10164–9. doi:10.1073/pnas.0703806104. PMC 1888575. PMID 17553960.
  14. ↑ 14.0 14.1 Kimoto S, Bazmi HH, Lewis DA (September 2014). "Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex in schizophrenia: contribution of altered regulation by Zif268". The American Journal of Psychiatry. 171 (9): 969–78. doi:10.1176/appi.ajp.2014.14010004. PMC 4376371. PMID 24874453.
  15. ↑ LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, Kostyk SK, Thomas K, Sarkar A, Siddiqui MS, Tatter SB, Schwalb JM, Poston KL, Henderson JM, Kurlan RM, Richard IH, Van Meter L, Sapan CV, During MJ, Kaplitt MG, Feigin A (April 2011). "AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial". The Lancet. Neurology. 10 (4): 309–19. doi:10.1016/S1474-4422(11)70039-4. PMID 21419704.
  16. ↑ Manto MU, Hampe CS, Rogemond V, Honnorat J (February 2011). "Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia". Orphanet Journal of Rare Diseases. 6 (3): 3. doi:10.1186/1750-1172-6-3. PMC 3042903. PMID 21294897.
  17. ↑ Mitoma, Hiroshi; Manto, Mario; Hampe, Christiane S. (2017-03-12). "Pathogenic Roles of Glutamic Acid Decarboxylase 65 Autoantibodies in Cerebellar Ataxias". Journal of Immunology Research. 2017: 1–12. doi:10.1155/2017/2913297. ISSN 2314-8861.
  18. ↑ Lorenzo LE, Magnussen C, Bailey AL, St Louis M, De Koninck Y, Ribeiro-da-Silva A (September 2014). "Spatial and temporal pattern of changes in the number of GAD65-immunoreactive inhibitory terminals in the rat superficial dorsal horn following peripheral nerve injury". Molecular Pain. 10 (1): 57. doi:10.1186/1744-8069-10-57. PMC 4164746. PMID 25189404.
  19. ↑ Dayalu P, Teener JW (November 2012). "Stiff Person syndrome and other anti-GAD-associated neurologic disorders". Seminars in Neurology. 32 (5): 544–9. doi:10.1055/s-0033-1334477. PMID 23677666.

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