Table of Contents Table of Contents
Previous Page  113 / 151 Next Page
Show Menu
Previous Page 113 / 151 Next Page
Page Background

Functional Assessment of Urinary Neuro-biogenic Amines—A COMPREHENSIVE GUIDE 


ditional isoforms are expressed during

early development. GAD67 synthesiz-

es GABA in the body of the neuron.

GAD65 is located in the axon terminals

near the nerve synapse, and provides ad-

ditional GABA as needed to meet the

functional demands of neuron activi-

ty. GAD67 expression is controlled by

the gene GAD1; GAD65 expression is

controlled by GAD2, a gene on a sepa-

rate chromosome. Early evidence from

a human twin study indicates that some

GAD1 haplotypes (gene groupings)

may be associated with increased risk

of neuropsychiatric disorders. The study

found no such association for GAD2

haplotypes. Animal studies associate

GAD function and behavior; the stud-

ies indicate that even subtle decreases

in GABA signaling may alter behavior.

Recently, a link has been made between

GAD deficiency and nonsyndromic cleft

lip or cleft palate.

GABA synthesis occurs in the cyto-

sol, and GABA is transported into syn-

aptic vesicles for storage by vesicular

GABA transporters (vGATs). Lithium

may increase GAD activity (animal stud-

ies). Once released, GABA is removed

from the neural synapse through active

transport back into the vesicles. GABA

re-uptake requires dedicated transmem-

brane transporters. In the CNS, GABA

uptake primarily occurs through the ac-

tivity of the plasma membrane GABA

transporter 1 (GAT1) which takes up

GABA through neuron and glial mem-

branes. GAT1 activity may be inhibited

by nitric oxide. A second GABA trans-

porter, GAT2, is found in the gastroin-

testinal tract, and GAT3 is expressed in

adult astroglia. Any GABA that remains

in the synapse is taken up by astroglia

and metabolized by GABA transaminas-

es (GABA-T), a group of three enzymes

that breaks GABA down (using various

substrates) into succinic semialdehyde,

glutamate and either glycine or alanine.

Succinic semialdehyde is then convert-

ed into succinate by SSADH in the mi-

tochondria for use in the tri-carboxylic

acid (TCA) cycle.

Amino acid decarboxylation reac-

tions in the gastrointestinal microbio-

ta are known to generate neuroactive

molecules which may not only con-

tribute to the levels of glutamate and

GABA, but affect gut function. GAD is

also expressed peripherally in pancreat-

ic B-cells, which are known to produce

GABA. GABA neurons are known to

innervate the pancreas. In vitro stud-

ies indicate that GAD65 may act as an

autoantigen, and may play a role in the

development of diabetes. Research con-

tinues into the function of GABA in the



GABA receptors are found through-

out the brain. There are two primary

groups of GABA receptors, GABA-A re-

ceptors are ionotropic, GABA-B recep-

tors are metabotropic. Animal studies

indicate that chronic administration of

antidepressants (such as phenelzine and

imipramine), benzodiazepines (such

as alprazolam, lorazepam, and diaze-

pam), and mood stabilizers (such as la-

motrigine) may differentially modulate

the gene expression of GABA receptor

subunits, particularly for GABA-A re-

ceptors. GABA receptor functions may

affect blood sugar levels and insulin


GABA-A receptors

Dysfunction of GABA-A receptor

subunits may affect memory, learning,

moods, fatigue, sedation level, stress-in-

duced depression, coordination, balance,

seizures, eating and alcohol use behav-