Glutamate decarboxylase

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For other uses of the abbreviation "GAD" in medicine, see Gad.
glutamate decarboxylase
Identifiers
EC number 4.1.1.15
CAS number 9024-58-2
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Glutamic acid decarboxylase 1
PDB GAD67.jpg
GAD67 derived from PDB 2okj
Identifiers
Symbol GAD1
Alt. symbols glutamate decarboxylase 1
(brain, 67kD); GAD67
Entrez 2571
HUGO 4092
OMIM 605363
RefSeq NM_000817
UniProt Q99259
Other data
EC number 4.1.1.15
Locus Chr. 2 q31
glutamic acid decarboxylase 2
Identifiers
Symbol GAD2
Alt. symbols GAD65
Entrez 2572
HUGO 11284
OMIM 4093
RefSeq NM_001047
UniProt Q05329
Other data
EC number 4.1.1.15
Locus Chr. 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[edit]

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[edit]

Diabetes[edit]

Both GAD67 and GAD65 are targets of autoantibodies in people who later develop type 1 diabetes mellitus or latent autoimmune diabetes.[7] [8][9] Injections with GAD65 has been shown to preserve some insulin production for 30 months in humans with type 1 diabetes.[10][11]

Schizophrenia and bipolar disorder[edit]

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]

Parkinson disease[edit]

The bilateral delivery of 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.[14]

Cerebellar disorders[edit]

Intracerebellar administration of GAD autoantibodies to animals increase the excitability of motoneurons and impairs the production of nitric oxide (NO), a molecule involved in learning. Epitope recognition contributes to cerebellar involvement.[15]

Stiff Person Syndrome[edit]

Anti-GAD antibodies are associated with Stiff-person syndrome but their causal role is not yet established.

Alteration by drugs[edit]

It was previously thought that pregabalin, an antiepileptic drug, increased neuronal GABA levels by producing a dose-dependent increase in glutamic acid decarboxylase activity. However it is currently believed that pregabalin exerts its activity by modulation of alpha-2-delta-subtype of neuronal calcium channels.[16] Extracts from Centella asiatica (gotu kola) and Valeriana officinalis (valerian) have a calming effect, likely by indirectly promoting GABAergic activity.[17]

References[edit]

  1. ^ Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ (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". Mol. Cell. Biol. 14 (11): 7535–45. PMC 359290. PMID 7935469. 
  3. ^ a b c d e f Pinal CS, Tobin AJ (1998). "Uniqueness and redundancy in GABA production". Perspect Dev Neurobiol 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". Proc. Natl. Acad. Sci. U.S.A. 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. ^ a b Battaglioli G, Liu H, Martin DL (August 2003). "Kinetic differences between the isoforms of glutamate decarboxylase: implications for the regulation of GABA synthesis". J. Neurochem. 86 (4): 879–87. doi:10.1046/j.1471-4159.2003.01910.x. PMID 12887686. 
  7. ^ Chandni R, Paul BJ, Udayabhaskaran V, Ramamoorthy KP (2013). "A study of non-obese diabetes mellitus in adults in a tertiary care hospital in Kerala, India". International Journal of Diabetes in Developing Countries 33 (2): 83–85. doi:10.1007/s13410-013-0113-7. 
  8. ^ Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, De Camilli P, Camilli PD (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. 
  9. ^ Kaufman DL, Erlander MG, Clare-Salzler M, Atkinson MA, Maclaren NK, Tobin AJ (1992). "Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus". J. Clin. Invest. 89 (1): 283–92. doi:10.1172/JCI115573. PMC 442846. PMID 1370298. 
  10. ^ 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". N. Engl. J. Med. 359 (18): 1909–20. doi:10.1056/NEJMoa0804328. PMID 18843118. 
  11. ^ "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. 
  12. ^ Woo TU, Walsh JP, Benes FM (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". Arch. Gen. 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 (2007). "Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars". Proc. Natl. Acad. Sci. U.S.A. 104 (24): 10164–9. doi:10.1073/pnas.0703806104. PMC 1888575. PMID 17553960. 
  14. ^ LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Askandar EN, et al (2011). "AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial". Lancet Neurol 10 (4): 309–19. doi:10.1016/S1474-4422(11)70039-4. PMID 21419704. 
  15. ^ Manto MU, Hampe CS, Rogemond V, Honnorat J (2011). "Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia". Orphanet J Rare Dis 6: 3. doi:10.1186/1750-1172-6-3. PMC 3042903. PMID 21294897. 
  16. ^ Errante LD, Petroff OA (July 2003). "Acute effects of gabapentin and pregabalin on rat forebrain cellular GABA, glutamate, and glutamine concentrations". Seizure 12 (5): 300–6. doi:10.1016/s1059-1311(02)00295-9. PMID 12810343. 
  17. ^ Awad R, Levac D, Cybulska P, Merali Z, Trudeau VL, Arnason JT (September 2007). "Effects of traditionally used anxiolytic botanicals on enzymes of the gamma-aminobutyric acid (GABA) system". Can. J. Physiol. Pharmacol. 85 (9): 933–42. doi:10.1139/Y07-083. PMID 18066140. 

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