DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

NPT1 (SLC17A1), cloned originally as a phosphate transporter
in humans, is expressed in abundance on the luminal membrane
of the proximal tubule as well as in the brain (Werner et al.,
1991). NPT1 transports PAH, probenecid, and penicillin G. It
appears to be part of the system involved in organic anion efflux
from tubule cell to lumen.
MRP2 (ABCC2), an ABC transporter, initially called the GS-
X pump (El-Sheikh et al., 2008; Ishikawa et al., 1990; Toyoda et al.,
2008), has been considered to be the primary transporter involved
in efflux of many drug conjugates such as glutathione conjugates
across the canalicular membrane of the hepatocyte. However, MRP2
is also found on the apical membrane of the proximal tubule, where
it is thought to play a role in the efflux of organic anions into the
tubular lumen. Its role in the kidney may be to secrete glutathione
conjugates of drugs, but it also may support the translocation (with
glutathione) of various non-conjugated substrates. In general, MRP2
transports larger, bulkier compounds than do most of the organic
anion transporters in the SLC22 family.
MRP4 (ABCC4) is found on the apical membrane of the
proximal tubule and transports a wide array of conjugated anions,
including glucuronide and glutathione conjugates (El-Sheikh et al.,
2008; Toyoda et al., 2008). However, unlike MRP2, MRP4 appears
to interact with various drugs, including methotrexate, cyclic
nucleotide analogs, and antiviral nucleoside analogs. Recent studies
in Mrp4 knockout mice suggest that the transporter is involved in
the renal elimination of the antiviral drugs adefovir and tenofovir
(Imaoka et al., 2006). Other MRP efflux transporters also have been
identified in human kidney, including MRP3 and MRP6, both on the
basolateral membrane. Their roles in the kidney are not yet known.
Polymorphisms of OATs. Polymorphisms in OAT1 and OAT3 have
been identified in ethnically diverse human populations (Leabman et
al., 2003; Srimaroeng et al., 2008). Two amino acid polymorphisms
(allele frequencies >1%) in OAT1 have been identified in African-
American populations. Three amino acid polymorphisms and seven
rare amino acid variants in OAT3 have been identified in ethnically
diverse U.S. populations (see www.pharmgkb.org ).
TRANSPORTERS INVOLVED IN
PHARMACODYNAMICS: DRUG
ACTION IN THE BRAIN
Neurotransmitters are packaged in vesicles in presynpatic
neurons, released in the synapse by fusion of the
vesicles with the plasma membrane, and, excepting
acetylcholine, are then taken back into the presyn -
aptic neurons or postsynaptic cells (see Chapter 8).
Transporters involved in the neuronal reuptake of the
neurotransmitters and the regulation of their levels in
the synaptic cleft belong to two major superfamilies,
SLC1 and SLC6. Transporters in both families play
roles in reuptake of γ-aminobutyric acid (GABA),
glutamate, and the monoamine neurotransmitters
norepinephrine, serotonin, and dopamine. These transporters
may serve as pharmacologic targets for
neuropsychiatric drugs (Gether et al., 2006; Hog et al.,
2006; Schousboe et al., 2004).
SLC6 family members localized in the brain and
involved in the reuptake of neurotransmitters into
presynaptic neurons include the norepinephrine transporters
(NET, SLC6A2), the dopamine transporter
(DAT, SLC6A3), the serotonin transporter (SERT,
SLC6A4), and several GABA reuptake transporters
(GAT1, GAT2, and GAT3) (Chen et al., 2004; Elliott
and Beveridge, 2005; Hediger, 2004). Each of these
transporters appears to have 12 transmembrane secondary
structures and a large extracellular loop with
glycosylation sites between transmembrane domains
3 and 4. These proteins are typically ~ 600 amino acids
in length. SLC6 family members depend on the Na +
gradient to actively transport their substrates into cells.
Cl – is also required, although to a variable extent
depending on the family member. Residues and
domains that form the substrate recognition and permeation
pathways are currently being identified.
Through reuptake mechanisms, the neurotransmitter
transporters in the SLC6A family regulate the concentrations
and dwell times of neurotransmitters in the
synaptic cleft; the extent of transmitter uptake
also influences subsequent vesicular storage of transmitters.
Many of these transporters are present in
other tissues (e.g., kidney and platelets) and may serve
other roles. Further, the transporters can function in
the reverse direction. That is, the transporters can
export neurotransmitters in an Na + -independent fashion.
The characteristics of each member of the SLC6A family
of transporters that play a role in reuptake of monoamine
neurotransmitters and GABA merit a brief description.
SLC6A1 (GAT1), SLC6A11 (GAT3), and SLC6A13 (GAT2). GAT1
(599 amino acids) is the most important GABA transporter in the
brain, expressed in GABAergic neurons and found largely on presynaptic
neurons (Høg et al., 2006; Schousboe et al., 2004). GAT1 is
found in abundance in the neocortex, cerebellum, basal ganglia,
brainstem, spinal cord, retina, and olfactory bulb. GAT3 is found
only in the brain, largely in glial cells. GAT2 is found in peripheral
tissues, including the kidney and liver, and within the CNS in the
choroid plexus and meninges.
GAT1, GAT2, and GAT3 are ~50% identical in amino acid
sequence. Functional analysis indicates that GAT1 transports GABA
with a 2:1 Na + :GABA – stoichiometry. Cl – is required. Residues and
domains responsible for the recognition of GABA and subsequent
translocation have been identified. Physiologically, GAT1 appears
to be responsible for regulating the interaction of GABA at receptors.
The presence of GAT2 in the choroid plexus and its absence in presynaptic
neurons suggest that this transporter may play a primary role
in maintaining the homeostasis of GABA in the CSF. GAT1 and
GAT3 are drug targets (Schousboe et al., 2004). GAT1 is the target
of the anti-epileptic drug tiagabine, which presumably acts to
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CHAPTER 5
MEMBRANE TRANSPORTERS AND DRUG RESPONSE