Biomedical Engineering Reference
In-Depth Information
certain brain cells.
1
The wide distributions of ENT1 and ENT2 in various cell types
and the ability of these transporters to transport both purine and pyrimidine nucle-
osides suggest that they play a primary role in nucleoside salvage pathways. The
ability of ENT2 to transport nucleobases indicates that this transporter may also con-
tribute to cellular uptake of hypoxanthine, a major salvageable purine nucleobase in
animals.
125
,
126
In addition, ENTs expressed in intracellular compartments may play a
role in organelle transport of nucleosides. It has been shown that some hENT1 is also
expressed in mitochondria
73
and thus may transport nucleoside into this organelle for
mitochondrial DNA synthesis. ENT3, an intracellular transporter expressed in lyso-
somes, has been postulated to export nucleosides produced by RNA degradation from
the lysosomes.
6
The CNTs are particularly abundant in epithelial cells of the intestine,
kidney, and liver. Expressed in the apical membranes, CNTs are thought to work in
concert with the basolaterally localized ENTs to mediate vectorial transepithelial flux
of nucleosides and therefore regulate total body homeostasis of nucleosides.
4
,
5
Another important physiological function of nucleoside transporters is related to
the purine nucleoside adenosine, a key signaling molecule that exerts profound effects
on many tissues and organs. Through binding to cell surface receptors (A
1
,A
2A
,A
2B
,
and A
3
), adenosine regulates a myriad of physiological processes, such as coronary
blood flow, vascular tone regulation, neurotransmitter release, platelet aggregation,
immunosuppression during cellular stress, and inflammation.
1-3
,
5
By influencing the
concentration of adenosine available to adenosine receptors, nucleoside transporters,
particular ENT1, play important regulatory roles in adenosine signaling. For example,
studies with rENT1 antibody revealed abundant expression of rat ENT1 protein in
the sinoatrial node, cardiac atrial, and ventricular cells, suggesting an important role
of this transporter in regulating the cardiovascular activity of adenosine.
127
In the
human brain, hENT1 and A1 receptors colocalize in various brain regions, indicating
an important role of hENT1 in the control of neuromodulatory action of adenosine in
the CNS.
71
Interestingly, studies of knockout mice lacking the
ENT1
gene suggested
that ENT1 has a physiological role in ethanol-associated behaviors via A1 adenosine
receptor.
128
The
ENT1
−
/
−
mice appeared phenotypically normal but consumed twice
as much alcohol as the wild-type mice.
128
Finally, recent studies have demonstrated
that ENT1 is involved in the anti-inflammatory effects of adenosine under stressful
conditions such as hypoxia.
111
,
112
,
114
Down-regulation of ENT1 appears to serve as
an innate protective mechanism during hypoxia.
8.6. CLINICAL SIGNIFICANCE OF NUCLEOSIDE TRANSPORTERS
The clinical significance of nucleoside transporters can be viewed in several aspects.
First, a number of anticancer nucleoside analogs rely on nucleoside transporters to
enter cells to reach their cellular targets. As such, the expression level of nucleo-
side transporters on the target cells is an important determinant for intracellular drug
bioavailability, and consequently, responsiveness to therapy. Second, if a drug is a
substrate for nucleoside transporters, the distribution of these transporters in various
tissues and organs, particularly the absorptive and excretory organs, may influence
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