Glutamate decarboxylase or glutamic acid decarboxylase 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. 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 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.
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. GAD67 is spread evenly throughout the cell
while GAD65 is localized to nerve terminals. 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. This function requires widespread, ubiquitous presence of GABA.
GAD65, however, synthesizes GABA for neurotransmission, 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, cysteine
string protein and Vesicular GABA transporter VGAT, which, as a complex,
helps package GABA into vesicles for release during neurotransmission. GAD67
is transcribed during early development, while GAD65 is not transcribed until
later in life. This developmental difference in GA67 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.
GAD67 and GAD65 are also regulated differently post-translationally. Both
GAD65 and GAD67 are regulated via phosphorylation, 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, while GAD65 is phosphorylated, and therefore regulated
by, protein kinase C. Both GAD67 and GAD65 are also regulated
post-translationally by Pyridoxal 5’-phosphate; GAD is activated when
bound to PLP and inactive when not bound to PLP. Majority of GAD67 is bound to
PLP at any given time, whereas GAD65 binds PLP when GABA is needed for
neurotransmission. 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. Injections with GAD65 has been shown to preserve
some insulin production for 30 months in humans with type 1 diabetes.
= Schizophrenia and bipolar disorder= Substantial dysregulation of GAD mRNA
expression, coupled with downregulation of reelin, is observed in schizophrenia
and bipolar disorder. 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.
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. 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. Since the dorsolateral prefrontal
cortex 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 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. = Cerebellar disorders=
Intracerebellar administration of GAD autoantibodies to animals increases the
excitability of motoneurons and impairs the production of nitric oxide, a
molecule involved in learning. Epitope recognition contributes to cerebellar
involvement. = Neuropathic pain=
Peripheral nerve injury of the sciatic nerve 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. Alteration by drugs
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. References
External links Media related to Glutamate decarboxylase
at Wikimedia Commons Genetics, Expression Profiling Support
GABA Deficits in Schizophrenia - Schizophrenia Research Forum, 25 June
2007.