Glutamate decarboxylase

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

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

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 schizophrenic patients 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 schizophrenic patients 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]

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.[17]

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.[18]

References

  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 359290Freely accessible. PMID 7935469.
  3. 1 2 3 4 5 6 Pinal CS, Tobin AJ (1998). "Uniqueness and redundancy in GABA production". Perspectives on developmental neurobiology. 5 (2–3): 109–118. PMID 9777629.
  4. ↑ Jin H, Wu H, Osterhaus G, Wei J, Davis K, Sha D, Floor E, Hsu CC, Kopke RD, Wu JY (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. 100 (7): 4293–4298. doi:10.1073/pnas.0730698100. PMC 153086Freely accessible. PMID 12634427.
  5. ↑ Wei J, Davis KM, Wu H, Wu JY (2004). "Protein Phosphorylation of Human Brain Glutamic Acid Decarboxylase (GAD)65 and GAD67 and Its Physiological Implications†". Biochemistry. 43 (20): 6182–6189. doi:10.1021/bi0496992. PMID 15147202.
  6. 1 2 Battaglioli G, Liu H, Martin DL (2003). "Kinetic differences between the isoforms of glutamate decarboxylase: Implications for the regulation of GABA synthesis". Journal of Neurochemistry. 86 (4): 879–887. 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 (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 (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 442846Freely accessible. 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". N. Engl. J. Med. 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 (2013 Sep 1). "Neuronal surface and glutamic acid decarboxylase autoantibodies in Nonparaneoplastic stiff person syndrome". JAMA Neurology. 70 (9): 1140–9. PMID 23877118. Check date values in: |date= (help)
  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 1888575Freely accessible. PMID 17553960.
  14. 1 2 Kimoto S, Bazmi HH, Lewis DA (2014). "Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex in schizophrenia: Contribution of altered regulation by Zif268". American Journal of Psychiatry. 171 (9): 969–78. doi:10.1176/appi.ajp.2014.14010004. 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 (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.
  16. ↑ Manto MU, Hampe CS, Rogemond V, Honnorat J (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. PMID 21294897.
  17. ↑ Lorenzo LE, Magnussen C, Bailey AL, St Louis M, De Koninck Y, Ribeiro-da-Silva A (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): 57–68. doi:10.1186/1744-8069-10-57. PMID 25189404.
  18. ↑ Dayalu, P (2012 Nov). "Stiff Person syndrome and other anti-GAD-associated neurologic disorders.". Semin. Neurol. 32 (5): 544–9. PMID 23677666. Check date values in: |date= (help)
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