CHAPTER 7
Neurotransmitters & Neuromodulators 133may be an epinephrine transporter. The other family is made
up of at least three transporters that mediate glutamate uptake
by neurons and two that transport glutamate into astrocytes.
These glutamate transporters are coupled to the cotransport of
Na
- and the countertransport of K
, and they are not depen-
dent on Cl
- transport. There is a debate about their structure,
and they may have 6, 8, or 10 transmembrane domains. One
of them transports glutamate into glia rather than neurons
(see Chapter 4).
There are in addition two vesicular monoamine trans-
porters, VMAT1 and VMAT2, that transport neurotrans-
mitters from the cytoplasm to synaptic vesicles. They are
coded by different genes but have extensive homology. Both
have a broad specificity, moving dopamine, norepinephrine,
epinephrine, serotonin, and histamine from the cytoplasm
into secretory granules. Both are inhibited by reserpine,
which accounts for the marked monoamine depletion pro-
duced by this drug. Like the neurotransmitter membrane
transporter family, they have 12 transmembrane domains,
but they have little homology to the other transporters.
There is also a vesicular GABA transporter (VGAT) that
moves GABA and glycine into vesicles and a vesicular ace-
tylcholine transporter.
Reuptake is a major factor in terminating the action of
transmitters, and when it is inhibited, the effects of transmit-
ter release are increased and prolonged. This has clinical con-
sequences. For example, several effective antidepressant drugs
are inhibitors of the reuptake of amine transmitters, and
cocaine is believed to inhibit dopamine reuptake. Glutamate
uptake into neurons and glia is important because glutamate
is an excitotoxin that can kill cells by overstimulating them
(see Clinical Box 7–1). There is evidence that during ischemiaTABLE 7–2
Mechanism of action of selected small-molecule transmitters.
Transmitter Receptor Second Messenger Net Channel Effects
Monoamines
Acetylcholine Nicotinic
↑
Na
+
, K
+
M
1,
M
3,
M
5
↑
IP
3
, DAG
↑
Ca
2+
M
2,
M
4
↓
Cyclic AMP
↑
K
+
Serotonin 5HT
1A
↓
Cyclic AMP
↑
K
+
5HT
1B
↓
Cyclic AMP
5HT
1D
↓
Cyclic AMP
↓
K
+
5HT
2A
↑
IP
3
, DAG
↓
K
+
5HT
2C
↑
IP
3
, DAG
5HT
3
↑
Na
+
5HT
4
↑
Cyclic AMP
Catecholamines
Dopamine D
1
, D
5
↑
Cyclic AMP
D
2
↓
Cyclic AMP
↑
K
+
,
↓
Ca
2+
D
3
, D
4
↓
Cyclic AMP
Norepinephrine
α
1
↑
IP
3
, DAG
↓
K
+
α
2
↓
Cyclic AMP
↑
K
+
,
↓
Ca
2+
β
1
↑
Cyclic AMP
β
2
↑
Cyclic AMP
β
3
↑
Cyclic AMP
Amino Acids
Glutamate Metabotropic
a
Ionotropic
AMPA, Kainate
↑
Na
+
, K
+
NMDA
↑
Na
+
, K
+
,Ca
2+
GABA GABA
A
↑
Cl- GABA
B
↑
IP
3
, DAG
↑
K
- ,
↓
Ca
2+
Glycine Glycine
↑
Cl
a
Eleven subtypes identified; all decrease cAMP or increase IP
3
and DAG, except one, which increases cAMP.