The liver is the only tissue not known
to express significant amounts of high-
affinity cationic amino acid transport
activity. Instead, the liver demonstrates
low-affinity cationic amino acid transport,
which is encoded by CAT2a, an alterna-
tively spliced variant arising from the
CAT2gene. Generally, CAT2a displays an
apparent affinity for arginine uptake that is
nearly tenfold lower (millimolar Kmvalues)
than that of the other CAT family members.
The low-affinity, but high-capacity trans-
port of CAT2a well matches its physio-
logical role of absorbing the relatively large
amounts of cationic amino acids from
dietary and endogenous sources that enter
the liver through portal vein drainage of
the intestinal tract.
EAAT family of anionic amino acid
transportersSystem XAG activity is defined as the
high-affinity, Na+-dependent, K+-coupled,
D-aspartate-inhibitable transport of L-
glutamate or L-aspartate. Currently, five
glutamate/aspartate family members have
been cloned from mammals that are
capable of system XAGactivity. In humans,
the proteins are referred to as EAAT1–
(excitatory amino acid transport), although,
as indicated in Table 1.3, alternative names
were used for the original non-human iso-
form clones. Functionally, the process for
transport by EAAT1–3 is thought to
involve extracellular binding and translo-
cation of one amino acid, one proton and
three sodium ions, with reorientation of
the transporter to the extracellular face of
the membrane being driven by the intracel-
lular-to-extracelluar counter-transport of
one potassium ion. In addition to the ion
flux associated with EAAT1–3, EAAT4 and
EAAT5 isoforms have a large inward chlo-
ride ion flux associated with their function,
which may aid in the re-establishment of
membrane potential by influencing cellular
chloride permeability. The capacity for glu-
tamate and aspartate uptake by EAAT4 and
EAAT5 is less than those for EAAT1–3.
Accordingly, it is thought that EAAT4 and
EAAT5 function as chloride channels that
are activated by the sodium-dependent
binding of anionic amino acids (Arriza et
al., 1997).
For the EAAT anionic family, the
predicted protein sequences show struc-
tural features typical of membrane solute
transporters, such as multiple membrane-
spanning domains and glycosylation sites.
Hydrophobicity analysis of EAAT family
members predicts that the N-terminus will
span the membrane six times. However, it
is not clear whether the large hydrophobic
C-terminal portion of the protein spans the
membrane. In contrast, the protein
sequences of most amino acid transporter
families are predicted to span the extra-
cellular membrane 10–12 times. Among
mammals, the sequence identity of a given
EAAT is typically >85%. In humans, across
transporters, the five cloned EAATs share
sequence identities of 36–46%. Compared
with human EAATs, a recently cloned
caterpillar EAAT isoform shares 37–42%
sequence identity with human EAAT1–
while salamander homologues of EAAT1,
EAAT2 and EAAT5 share 87, 84 and 58%
sequence identities, respectively.
EAAT1–4 are highly expressed in brain
tissue, but with distinct patterns of distrib-
ution. In the brain, EAAT1 and EAAT2 rep-
resent glial-specific glutamate transporters,
whereas EAAT3 and EAAT4 represent neu-
ron-specific activities. Accordingly, EAAT
and EAAT2 are involved in neurotrans-
mission whereas EAAT3 and EAAT4 are
thought to be responsible for more general
metabolic functions of brain tissues. A
reduction in the capacity to resorb gluta-
mate from synaptic clefts has been associ-
ated with neuron degeneration in sporadic
amyotrophic lateral sclerosis (Lou
Gehrig’s disease). Recent work has identi-
fied that this loss in glutamate transport
capacity is due solely to reduced expres-
sion of EAAT2, resulting from the aberrant
processing of EAAT2 mRNA (Lin et al.,
1998).
EAAT3 is the most widely distributed
of the glutamate transporters outside of the
brain. For example, in the rabbit, EAAT
mRNA is expressed in the duodenum,Amino Acid and Peptide Transport Systems 11