Biomedical Engineering Reference
In-Depth Information
14.2.3 S
UBSTRATE
S
PECIFICITY
AND
B
INDING
S
ITES
IN
SLC6 N
EUROTRANSMITTER
T
RANSPORTERS
The biogenic amine transporters include DAT, the norepinephrine transporter (NET), and the SERT.
Among these, DAT and NET display marked overlapping selectivity for dopamine and norepineph-
rine; hence, DAT transports dopamine and norepinephrine with similar efi cacy, and the apparent
afi nity for dopamine is only a few folds higher than that for norepinephrine (Figure 14.4). Moreover,
NET transports dopamine with 50% of the efi cacy seen for norepinephrine, and the apparent afi nity
for norepinephrine is even a few folds higher than that for dopamine. Accordingly, their classii cation
as DAT and NET seems primarily determined by their localization to dopaminergic and noradrenergic
neurons, respectively, rather than by their distinct substrate specii city. In contrast, the SERT displays
high specii city toward 5-HT although it has been shown that the SERT can transport dopamine if
present in very high concentrations. The GABA transporters (GAT-1 to GAT-3) and the glycine trans-
porters (GlyT-1 and -2) all display high specii city for their respective endogenous substrates; however,
GAT-2 and GAT-3 can also transport beta-alanine, the only beta-amino acid that occurs naturally, and
GlyT1 can transport the naturally occurring
N
-methyl-derivative of glycine, sarcosine.
The availability of the LeuT
Aa
structure has provided the i rst reliable hypothesis for the loca-
tion of the primary substrate-binding site in this class of transporters. The most striking feature of
Substrates
OH
N
CH
3
N
+
NH
2
NH
2
N
NH
2
CH
3
O
CH
3
HO
HO
HO
CH
3
O
OH
OH
NH
2
Serotonin
(5-HT)
Dopamine
Norepinephrine
Amphetamine
MPP
+
MDMA (Ecstacy)
Antagonists
CH
2
CH
2
CH
2
CH
3
Cl
N
CH
3
H
3
C
O
HO
N
CH
3
N
O
H
3
C
O
O
N
O
N
O
N
X
O
O
N
F
F
GBR-12935
(Royal Gist-Brocades)
RTI-55
X = I
Cocaine
JHW 007
Mazindol
CFT
X = F
Tropane class
1,4-Dialkylpiperazine class
Mazindol class
F
X
2
X
1
F
O
H
3
C
N
N
O
O
O
CH
3
H
3
C
N
O
CH
3
F
3
C
Imipramine
X
1
: N, X
2
: - (CH
2
)
3
N(CH
3
)
2
Desipramine X
1
: N, X
2
: - (CH
2
)
3
NCH
3
Nortriptyline X
1
: C, X
2
: = CH(CH
2
)
2
NHCH
3
Tricyclic antidepressives
O
O
H
NC
Citalopram
Fluoxetine
Paroxetine
Methylphenidate
SSRIs
Methylphenidate class
O
CH
3
S
OH
H
O
CH
3
N
N
CH
3
CH
3
Duloxetine
Venlafaxine
SNRIs
FIGURE 14.4
Chemical structures of most common substrates and antagonists for the DAT, NET, and
SERT. SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin-norepinephrine reuptake inhibitors.
