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Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONBBB amino acid transport...Anionic amino acid transport...System y+System LSUMMARYREFERENCES |
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KEY WORDS: • blood-brain barrier • glutamate • transport • endothelium • aspartate
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONBBB amino acid transport...Anionic amino acid transport...System y+System LSUMMARYREFERENCES |
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); it also
contributes to learning and memory through use-dependent changes in
synaptic efficacy, such as long-term potentiation and long-term
depression. Under pathologic conditions, excess release of
L-glutamic acid and other excitatory amino acids can lead
to excitotoxic lesions in brain from overexcitation of nerve cells.
Excitotoxicity is thought to play an important role in the neural
damage that occurs in diseases such as trauma, stroke, epilepsy and
hypoglycemia. Comparable damage can be produced by direct
administration of L-glutamate to the nervous system and,
under select conditions, by peripheral administration of very high
doses of L-glutamate to infant animals (Meldrum 1993
).
Under normal conditions, most free L-glutamic acid in brain
is derived from local synthesis from L-glutamine and
Kreb’s cycle intermediates. A considerable fraction is also derived
from recycling from brain protein. In synaptic terminals,
L-glutamate is stored in vesicles and released via a
calcium-dependent mechanism. Once in the synaptic cleft,
L-glutamate binds and activates postsynaptic glutamate
receptors. Although many different glutamate receptor subtypes have
been identified (Nakanishi 1992
), the ionotropic
glutamate receptors have been studied most extensively and are
subdivided into three classes on the basis of sensitivity to the
agonists, kainate, quisqualate or
N-methyl-D-aspartate
(NMDA).2
The NMDA receptor functions as a gatekeeper for sodium and calcium, and
has five separate binding sites, each of which is affected by different
substrates capable of altering receptor affinity. The action of
L-glutamate is terminated by removal from the synaptic
cleft by neuronal presynaptic and glial high affinity reuptake systems,
several of which have been cloned (Castagna et al. 1997
,
Kanai et al. 1994
, Kanai 1997
). These
active sodium-dependent transport systems maintain a very large
gradient of L-glutamate from the intracellular to the
extracellular space (5000- to 10,000-fold) so that brain extracellular
L-glutamate concentrations are normally quite low, with
cerebrospinal fluid concentration averaging <0.4 µmol/L
(Ferrarese et al. 1993
).
Given the critical role of L-glutamate in neural function, it is not surprising that a greater level of regulation is required of brain L-glutamate concentration than that observed in most other tissues. This regulation must include control of both extracellular as well as intracellular free L-glutamate concentrations because L-glutamate acts predominantly at the extracellular synaptic cleft. Plasma L-glutamate concentrations fluctuate during the day as a result of changes in diet, metabolism and protein turnover. If these changes were transferred directly to the brain interstitial space, they would have disrupting effects on neuronal synaptic communication.
The isolation and protection of the brain is accomplished in good part
through the presence and function of the "blood-brain barrier"
(BBB). The BBB is a system of tissue sites, including brain vascular
endothelial cells, choroid plexus epithelial cells and arachnoid
membrane; together, they restrict and regulate the flux of substrates
between the circulation and the central nervous system
(Pardridge 1998
). The barrier at each site is formed by
a single layer of cells that are joined together by multiple bands of
tight junctions. These tight junctions seal off the paracellular
diffusion space; thus, to cross the barrier, most solutes must either
dissolve in and diffuse across the lipoid cellular membranes of the
barrier cells or be transported across by selected BBB carriers. As a
consequence, the passive influx of most polar solutes, such as
L-glutamate, is quite limited at the BBB and is <1% of
that occurring at the blood vessels of most other tissues. To
compensate for the limited passive exchange, the cells of the BBB
contain high levels of 20 or more specific transport systems that
regulate the flux of key solutes from blood into brain interstitial
fluid and cerebrospinal fluid and back out again.
In this paper, we summarize the current status of knowledge of amino acid transport at the BBB. Primary focus will be on the transporters at the brain capillary membranes because the capillaries, due to their large surface area, are the primary site of exchange for most solutes between brain interstitial fluid and the circulation. Further, the brain penetration of other acidic (or anionic) amino acid analogs will be discussed, as well as the changes that occur in brain permeation and transport during development.
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BBB amino acid transport systems |
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TOPABSTRACTINTRODUCTIONBBB amino acid transport...Anionic amino acid transport...System y+System LSUMMARYREFERENCES |
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summarizes the current state of knowledge on their distribution and
activity at the capillary luminal and abluminal membranes. These
transport systems differ in substrate specificity, inhibition by model
ligands (e.g., methyl-aminoisobutyric acid and
2-aminobicyclo[2,2,1]heptane-2-carboxylic acid [BCH]), and
transport dependence on sodium (Smith and Stoll 1998
).
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, Oldendorf and Szabo 1976
, Pardridge 1979
). These transporters include the following: 1)
System L, which mediates high affinity, sodium-independent uptake
of zwitterionic amino acids with "large, neutral" side chains,
including L-leucine, L-phenylalanine,
L-tryptophan, L-tyrosine,
L-isoleucine, L-methionine and
L-valine; 2) System y+,
which mediates moderate affinity, sodium-independent uptake of
amino acids with cationic side chains, including
L-arginine, L-lysine and
L-ornithine; 3) System T, which mediates high
affinity, low capacity transport of thyroid hormones
(T3 and T4); and
4) System x-, which mediates
sodium-independent, high affinity uptake of amino acids with
anionic side chains, including L-glutamate and
L-aspartate.
The System L and y+ carriers are sodium
independent and mediate facilitated exchange at both the capillary
luminal and abluminal membranes. Their function is necessary to deliver
dietary essential neutral and basic amino acids that cannot be
synthesized within the brain (Betz and Goldstein 1978
,
Momma et al. 1987
, Sánchez del Pino et al. 1992
and 1995
, Smith et al. 1987
, Stoll et al. 1993
). In contrast, L-glutamate and
L-aspartate, which can be synthesized readily in brain,
show much lower rates of uptake into brain at the BBB (Al-Sarraf et al. 1995
and 1997b
, Benrabh and Lefauconnier 1996
). For these "dietary nonessential" amino acids, brain
supply is governed more by intracerebral synthesis and breakdown.
Table 1
summarizes transport Vmax and
Km values for amino acid uptake into
brain at the BBB as measured with the in situ rat brain perfusion
technique. Transport rates were determined for each amino acid in the
absence of competitors. As shown in Table 1
, Systems L,
y+ and x- each mediate the
uptake of two or more amino acids; thus there is the potential for
competition among substrates. Actually, competition is quite important
because, as shown in Table 1
, the plasma concentration for most of the
amino acid substrates equals or exceeds the corresponding transport
Km. As a consequence, each of the
three transport systems is predicted to be nearly saturated with amino
acid substrates as a group at normal plasma concentrations. Kinetic
calculations for System L reveal a saturation percentage of >95% when
all nine or so amino acid substrates are included. Due to transport
saturation, individual amino acids must compete for transport, such
that the apparent Km for uptake from
plasma is 3- to 20-fold greater than the true
Km from saline measured in the absence
of competitors. The apparent Km is
defined as Km(app) = Km[1 +
(Ci/Kmi)],
where Ci is the plasma concentration
of each competing amino acid and Kmi
is the corresponding transport Km for
that amino acid. Transport saturation makes the brain amino acid
delivery selectively vulnerable to large imbalances in plasma amino
acid concentration such as those that occur in the hyperaminoacidemias,
e.g., phenylketonuria and maple syrup disease (Smith and Stoll 1998
).
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recently reported that
glutamine is actually taken up into brain by a separate
sodium-dependent mechanism at the BBB, which they identified
tentatively as System N. In other tissues, System N mediates the
sodium-dependent transport of L-glutamine,
L-histidine and L-asparagine. Lee et al. (1998)
also found evidence for the presence of a separate
glutamine transporter distinct from System L at the luminal membrane of
the BBB with the use of isolated bovine brain endothelial cell membrane
vesicles. However, in that study, the sodium-dependent System N
transport was confined to the brain capillary abluminal membrane and
was suggested to have a critical role in glutamine efflux from the
central nervous system, not uptake. Further research is needed to
clarify this discrepancy.
In vitro studies have also provided evidence for the presence of five
other sodium-dependent, active transport systems for amino
acids at the brain capillaries, including System A, System
Bo+, System ASC, System ß, and System X-
(Betz and Goldstein 1978
, Lee et al. 1998
, Sánchez del Pino et al. 1995
,
Tayarani et al. 1987
and 1989
). Systems A, ASC,
X- and Bo+ are proposed to be located
primarily at the capillary abluminal membrane (Fig. 1)
and actively
transport amino acid substrates into the cerebrovascular endothelial
cell for efflux from brain extracellular fluid. Systems A and ASC show
preference for small neutral amino acids (e.g., L-alanine,
L-serine, L-cysteine), whereas System
Bo+ expresses affinity for both neutral and basic amino
acids (Guidotti and Gazzola 1992
). ß-Amino acids
(e.g., ß-alanine and taurine) are shuttled into brain capillaries by
a low capacity, Na+- and Cl-- dependent
transport carrier (System ß) (Tamai et al. 1995
,
Tayarani et al. 1989
). System X- mediates
sodium-dependent transport of anionic amino
acids-L-glutamate and L-aspartate. Although the
results are preliminary, there is clear evidence of amino acid
transport polarity at the BBB with selective distribution of some
carriers on the abluminal membrane.
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Anionic amino acid transport systems |
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TOPABSTRACTINTRODUCTIONBBB amino acid transport...Anionic amino acid transport...System y+System LSUMMARYREFERENCES |
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and 1997b
, Benrabh and Lefauconnier 1996
,
Oldendorf and Szabo 1976
). Because transport was
measured from plasma into brain, it is presumed that the saturable
carrier is located at the BBB capillary luminal membrane. The exact
protein that mediates this uptake has not been identified.
L-Glutamate uptake at the abluminal membrane of the
capillary endothelial cell was shown by Hutchinson et al. (1985)
and Lee et al. (1998)
to be mediated by a
sodium-dependent saturable mechanism similar to that of System
X-. A family of sodium-dependent anionic
amino acid transporters have recently been cloned and identified in
brain, but not localized to the BBB (Kanai et al. 1994
).
The molecular identification of the specific anionic amino acid
transporters at the BBB remains to be determined.
The transport capacity for saturable influx of L-glutamate
into brain is quite low compared with that of the System L and
y+ carriers (Table 1)
. This, together with the
fact that the glutamate carrier is >80% saturated at normal plasma
concentrations, predicts that anionic amino acid flux rates into brain
are small (Al-Sarraf et al. 1997a
and 1997b
,
Segal et al. 1990
). Hawkins et al. (1995)
reported that the brain uptake "permeability-surface area" for
L-[14C]glutamate from normal plasma
is ~7 µL/(min · g), corresponding to an influx rate of
0.67 nmol/(min · g). This flux rate is 5- to 10-fold less than that
of most of the large neutral and basic amino acids listed in Table 1
. A
portion of glutamate is mediated by a nonsaturable mechanism with a
Kd of 2 µL/(min · g)
(Pardridge 1979
).
A number of studies have examined the influence of acute elevations in
plasma L-glutamate concentration on brain
L-glutamate content. Most have found that in brain regions
with an intact BBB, L-glutamate content is fairly
independent of plasma L-glutamate concentration
(Price et al. 1981
and 1984
). The brain intracellular
L-glutamate pool, however, is quite large (4–15 mmol/kg
wet weight), and may mask changes in brain extracellular glutamate,
which is normally in the range of 0.2–5 µmol/L. With the
use of microdialysis, Bogdanov and Wurtman (1994)
found significant elevations in brain
extracellular fluid L-glutamate concentration after large
systemic doses of monosodium glutamate that would be expected to raise
plasma L-glutamate concentration into the millimolar level.
These results must be interpreted with caution, however, because
Westergren et al. (1995)
reported that brain
microdialysis compromises the integrity of the BBB, allowing greater
passive leakage of glutamate into brain. It is likely that with large
systemic dosing, some net uptake of L-glutamate occurs in
brain. Evaluation of the relationship between cerebrospinal fluid and
plasma glutamate may help resolve this controversy.
A second high affinity glutamate transport system has been demonstrated
at the choroid plexus epithelium (Km, 2–3
µmol/L), which may provide an alternate route for
glutamate influx into brain (Preston and Segal 1992
,
Segal et al. 1990
). Less is known of glutamate efflux
from the central nervous system. Pardridge (1979)
has
speculated that an active efflux pump for glutamate exists at the
blood-brain barrier and may contribute to the regulation of brain
extracellular fluid glutamate concentration. Both Hutchinson et al. (1985)
and Lee et al. (1998)
detected
sodium-dependent active components of glutamate transport with the
use of in vitro brain endothelial preparations that allow evaluation of
transport at the capillary abluminal membrane. Both suggested that the
sodium-dependent carrier functions in vivo to transport glutamate
from brain. However, more work on this is required to confirm the
issue.
Al-Sarraf et al. (1997b)
examined the kinetics of
anionic amino acid uptake in 1-wk-old and adult rats and found that for
the BBB Vmax for both
L-glutamate and L-aspartate is elevated in
infant animals. This occurs even though the capillary density in brain
is considerably lower in infant animals. No marked alteration was
observed in passive BBB permeability, suggesting that if there were
age-dependent changes in anionic amino acid transport at the BBB,
they were due to alterations in carrier activity. The transport
selectivity of the anionic amino acid carriers at the BBB has not been
examined closely. BBB transfer rates for several amino acid analogs
that have been studied (e.g., domoic acid, kynurenic acid,
ß-methyl-amino-alanine) are quite low and appear not to use
the BBB anionic amino acid carrier (Fukui et al.1991
,
Preston and Hynie 1991
, Smith et al. 1992
).
Although the BBB helps protect most of the brain from changes in
circulating plasma L-glutamate, there are a few brain areas
that do not contain a BBB (Fig. 2
) and do allow rapid L-glutamate uptake from the
circulation (Hawkins et al. 1995
). These are known
collectively as "the circumventricular organs" and include the
median eminence, area postrema, subfornical organ, subcommissural
organ, pineal gland, neurohypophysis and organum vasculosum of the
lamina terminalis (Gross and Weindel 1987
). Brain uptake
rates for small solutes in these areas exceed those of normal brain by
10- to 1000-fold (Gross et al. 1987
, Gross 1991
, Hawkins et al. 1995
, Shaver et al. 1992
). Once within brain extracellular fluid, solutes can move
into adjacent brain areas via intercellular diffusion or via flow along
the Virchow-Robin spaces. Such movement has been documented for
glutamate and aspartate in animals after high dose amino acid
administration (Price et al. 1981
and 1984
). The net
result is that certain areas of the brain are vulnerable to acute
fluctuations in plasma glutamate concentration of large magnitude as a
result of "flooding" from the circumventricular organs.
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System y+ |
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TOPABSTRACTINTRODUCTIONBBB amino acid transport...Anionic amino acid transport...System y+System LSUMMARYREFERENCES |
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as part of the search for the
host cell protein responsible for infection by the murine ecotropic
leukemia virus. The normal physiologic function of this retrovirus
receptor was unknown at the time. However, on the basis of a predicted
structural homology with yeast histidine and arginine permeases,
Kim et al. (1991)
and Wang et al. (1991)
independently injected the cRNA for the receptor into frog oocytes and
demonstrated that it led to enhanced amino acid transport activity with
characteristics closely matching those previously reported for System
y+. The deduced amino acid sequence of the
retroviral receptor cDNA clone revealed a 622 amino acid glycoprotein
with a predicted molecular mass of 67 kDa. After
N-glycosidase treatment, however, the apparent molecular
mass was 60–65 kDa. Hydropathy profiling predicted 12–14
transmembrane-spanning regions, similar to that of the previously
cloned facilitative glucose transporter, GLUT1. Subsequently, the
corresponding human and rat genes for CAT-1 were cloned and shown to
share >88% sequence identity with the murine sequence (Puppi and Henning 1995
, Stoll et al. 1993
,
Yoshimoto et al. 1992
). The human gene maps to
chromosome 13q12-q14 and consists of 10 introns and 11 exons
(Albritton et al. 1992
). The human cDNA sequence
predicts a 629 amino acid protein with a comparable 12–14
transmembrane-spanning regions. In rats, the primary CAT-1 mRNA
size is 7.9 kb, with a smaller band often seen at 3.4 kb in some
tissues (Smith and Stoll 1998
).
Stoll et al. (1993)
demonstrated by RNase protection
assay that CAT-1 is highly expressed at the BBB, with a >40-fold
enhancement of mRNA for the protein in brain capillaries compared with
whole brain or "capillary-depleted" brain. mRNA for CAT-1 is not
ubiquitous among tissues and varies significantly; the highest values
are found in bone marrow, intestine, kidney, testes and brain, with
essentially no expression in liver (Kakuda et al. 1993
,
Kim et al. 1991
, Puppi and Henning 1995
,
Smith and Stoll 1998
, Stoll et al. 1993
).
Figure 3
shows a Northern blot of CAT-1 in brain capillaries, brain and other
tissues.
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and 1993b
, Kakuda et al. 1993
). CAT-2 is
differentially expressed in tissues, including brain, but does not
appear to be enriched at the BBB, where message levels are <10% of
that of CAT-1 (Smith and Stoll 1999
). CAT-3 is
highly expressed in brain and readily discriminates between
L-lysine and L-arginine on the basis of
affinity (difference of approximately twofold).
A CAT-1 knockout mouse model has been developed in which targeted
mutagenesis was used to alter the domain of the protein that is
critical for virus binding and produce a germ line with null transport
activity (Perkins et al. 1997
). Homozygous pups with
this mutation were 25% smaller than normal, very anemic and died on
the day of birth. The results suggest a critical role in hematopoiesis
and growth during development.
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System L |
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TOPABSTRACTINTRODUCTIONBBB amino acid transport...Anionic amino acid transport...System y+System LSUMMARYREFERENCES |
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and later shown by Oldendorf and colleagues
to contribute to the brain uptake of 14 of the 16 primary neutral amino
acids (Oldendorf 1971
, Oldendorf and Szabo 1976
, Pardridge 1983
). The carrier appears to
operate principally via a sodium-independent, substrate-coupled
antiport, although it can mediate net influx (Guidotti and Gazzola 1992
).
System L at the BBB shares many of the characteristics of the L System
transporter in other tissues, including inhibition by BCH
(Aoyagi et al. 1988
, Hargreaves and Pardridge 1988
, Smith et al. 1987
). The two carriers
differ, however, in apparent transport "affinity"
(1/Km) for most substrates. For
example, the Km for
L-phenylalanine uptake into brain (~10–20
µmol/L; Momma et al. 1987
,
Sánchez del Pino et al. 1995
, Shulkin et al. 1995
) is 100-1000 times less than that in other tissues. On
the basis of this difference, it has been proposed that the
blood-brain barrier L System represents a separate isoform,
designated System L1.
Several genes have been identified that enhance neutral amino acid
uptake when their mRNA is injected into cells. One encodes for a cell
surface protein, 4F2hc, also known as CD 98, and has been demonstrated
to enhance System L activity in cells (Bertran et al. 1992
, Bröer et al. 1995
and 1997
,
Palacín, 1994
). Recently, a System L cDNA was
cloned by both Kanai et al. (1998)
and Mastroberardino et al. (1998)
and shown to encode for a ~41-kDa protein (LAT) with
multiple transmembrane-spanning regions, which operates in
conjunction with 4F2hc. The two proteins are reportedly linked by a
disulfide bridge. The 4F2 complex was identified first in a human
T-cell line as a heterodimer composed of an 85-kDa glycosylated
heavy chain (4F2hc) with a single transmembrane-spanning region
with a disulfide linkage to a 45-kDa nonglycosylated light chain.
This smaller subunit was proposed by Palacín (1994)
to be a transporter. The cDNA isolated by Kanai encodes
for a protein that mediates BCH-sensitive neutral amino acid
transport, when expressed in Xenopus oocytes
(Km for L-phenylalanine is 20
µmol/L). Message for the protein was found in multiple
tissues including brain. The functional relation between the
transporter and the 4F2hc is not precisely understood. It has been
suggested, however, that 4F2hc is a required regulatory or modulator
subunit for the transporter complex.
Consistent with the proposed role of 4F2hc in System L transport into
brain, message for 4F2hc was found in mRNA from isolated rat brain
capillaries, as well as in whole rat brain (Smith and Stoll 1999
). Similarly, Boado et al. (1999)
have
demonstrated high level expression of the mRNA for the light chain of
the L transporter (LAT) at the blood-brain barrier. Expression of 4F2hc
also decreased during postnatal development in the rat, as expected
from L-System transport studies.
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SUMMARY |
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TOPABSTRACTINTRODUCTIONBBB amino acid transport...Anionic amino acid transport...System y+System LSUMMARYREFERENCES |
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FOOTNOTES |
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2 Abbreviations used: BBB, blood-brain barrier; BCH, 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid;
CAT, cationic amino acid transporter; NMDA, N-methyl-D-aspartate.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONBBB amino acid transport...Anionic amino acid transport...System y+System LSUMMARYREFERENCES |
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