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species, it differs in its specificity for carnitine transport. In rat, this transporter does
not mediate Na
+
-coupled carnitine transport to a significant extent,
10
but in mice the
carnitine transport is Na
+
dependent.
9
Tissue Distribution and Cellular Membrane Localization
Wu et al.
10
demonstrated
by in situ hybridization that rat Octn1 mRNA was expressed in a wide variety of rat
tissues, including the liver, intestine, kidney, brain, heart, and placenta. Large species
differences exist with regard to localization and function of OCTN1. OCTN1 could
not be detected in liver from adult humans, whereas in rats, that is the site with the
strongest expression.
10
Koepsell et al.
5
suggested that hOCTN1 has a luminal location
in brush border membranes of renal proximal tubules, where it may be engaged in
cation excretion in different species. Since it transports in both directions, OCTN1
may also participate in the reabsorption of organic cations. Also, carnitine uptake was
Na
+
dependent for mouse Octn1 but not for rat Octn1.
9
,
11
Loss of function mutations
in hOCTN1 would predictably increase the nephrotoxic potential of cationic drugs that
enter proximal tubules. Pharmaceutical up-regulation of hOCTN1 might improve the
renal excretion of cationic drugs or xenobiotics without increasing their intracellular
concentrations.
Xuan et al.
13
have used anti-mOctn1 antibody to demonstrate the expression of
OCTN1 in sperm. They have also shown a low-affinity carnitine uptake in sperm
with a
K
m
of 412
M, which is consistent with values demonstrated previously for
OCTN1 in different tissues and species. Evidence has been presented of the existence
in sperm of all three OCTN species. It has been suggested that OCTN1 may serve an
important role in the intracellular shuttling of acylcarnitines in sperm mitochondria.
μ
3.2.2. OCTN 2
Structure-Function Relationships
Among the organic cation transporters, OCTN2
is identified as the most important carnitine transporter. Koepsell et al.
5
have re-
viewed extensively the biochemistry and physiology of carnitine transport mediated
by OCTN2 and other OCTN transporters. OCTN2 is a Na
+
/carnitine cotransporter
with a high affinity for carnitine but can function alternatively as a polyspecific and
Na
+
-independent cation uniporter.
14
-
17
Na
+
-dependent transport of L-carnitine by
OCTN2 is electrogenic and to some degree stereospecific.
16
,
18
Ligand Specificity and Drug Substrates
Several uptake measurements have shown
that human OCTN2 has an apparent
K
m
of4to5
M for L-carnitine,
14
,
16
μ
and it
exhibits half-maximal concentrations for Na
+
activation between 2 and 19
M.
16
,
18
,
19
Therefore, the molecule responsible for the high-affinity Na
+
/L-carnitine cotransport
activity is likely to be represented by OCTN2. This activity is observed both in plasma
membrane vesicles from skeletal muscle and in brush border membrane vesicles from
the kidney and intestine.
20
-
23
Short-chain acyl esters of carnitine are also transported
by hOCTN2 with high affinity in the presence of Na
+
with a
K
m
around 8.5
μ
M.
18
μ
-lactam antibiotic
24
in the
hOCTN2 can also transport cephaloridine, a zwitterionic
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