stoichiometries of 1:1, 2:1 and 1:1 for
neutral, acidic and basic dipeptides (Steel
et al., 1997). Given that the enterocyte
microenvironment of the apical membrane
is maintained between pH 5.5 and 6.3,
these findings suggest that PepT1 will bind
preferentially to neutral and acidic dipep-
tides. In contrast, other expression studies
indicate that the influence of pH on PepT1
and PepT2 function is to increase the
velocity of transport, not the affinity of the
transporter for its substrate (Brandsch et
al., 1997).
Rabbit PepT1 mRNA has been
identified in the greatest quantity in
epithelial cells of the small intestine, with
lesser amounts in the liver and kidney
tissue, and trace amounts in several brain
tissues (Fei et al., 1994). In contrast, the
strongest expression of PepT2 is in the
kidney, with weaker expression in brain,
lung, liver, heart and spleen. The dual
expression of PepT1 and PepT2 in the
kidney is consistent with the biochemic-
ally defined high- and low-affinity peptide
transport systems (Daniel et al., 1992).
Because the concentration of peptides is
thought to increase from the proximal to
distal nephron, future immunohisto-
chemical research is expected to reveal that
PepT2 (high-affinity, low-capacity) will be
expressed primarily in the proximal
nephron region, while PepT1 (low-affinity,
high-capacity) will be expressed in the
distal region of nephrons (Leibach and
Ganapathy, 1996).
In the liver, the degree to which
peptides are absorbed is controversial.
Mediated uptake of carnosine and glycyl-
sarcosine has been characterized in
hamster liver slices (Matthews, 1991).
However, the quantitative importance of
hepatic peptide absorption is questioned
by the observation that rat hepatocytes
were incapable of absorbing dipeptides
that are less resistant to hydrolysis than
glycylsarcosine and carnosine (Lochs et
al., 1986). Instead, the absorption of pep-
tide-bound amino acids occurs only after
hydrolysis to their constituent amino
acids. Therefore, the fact that the liver of
rabbits contained mRNA for PepT1 (Fei et
al., 1994) and PepT2 (Boll et al., 1996)
suggests that species difference exists for
tissue-specific peptide transporter expres-
sion. Alternatively, the expression of
transporter protein may be limited to
membranes other than the plasma mem-
brane. In support of this hypothesis, low-
affinity peptide transport activity has
been demonstrated in the lysosomal
membranes of rat hepatocytes using
Gly-Gln (Thamotharan et al., 1996). Also,
the presence of PepT1 mRNA does not
necessarily mean that PepT1 protein is
expressed, or that the amount expressed is
below detection. For example, even
though EAAT4 mRNA is detectable in rat
placenta, EAAT4 protein is not (Matthews
et al., 1998a). Finally, the expression of
peptide transporters may be limited to a
small subset of liver cells and/or in subcel-
lular membranes, perhaps, in a manner
analogous to the expression of system
XAGactivity by only the pericentral hepa-
tocytes, which constitute only 7% of
all hepatocytes (Kilberg and Haussinger,
1992). This controversy illustrates the
point that even though molecular tech-
niques can localize the expression of
transporter mRNA and protein, biochemi-
cal assays are necessary to gauge the phys-
iologic importance of their presence.Unidentified transport proteinsDespite the tremendous success in the
cloning and identification of many proteins
responsible for the transport of amino acids
and peptides, the proteins responsible for
several physiologically important transport
activities have not been cloned. Much of
the cationic and zwitterionic amino acid
transport across the apical membrane of
polarized cells occurs by system Bo,+
activity. The eventual cloning of cDNAs
that encode this activity, which is the only
described Na+-dependent activity capable
of the transport of both cationic and
neutral amino acids, should yield
important insights into the teleologic
development of amino acid transporters.
System L activity, one of the first to beAmino Acid and Peptide Transport Systems 15