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

374
Presynaptic
neuron
11 10
7
Neurotransmitter
9
Ca 2+
2
SECTION II
AP
1
4
NT
5
3
6
8
Glial
cell
NEUROPHARMACOLOGY
Postsynaptic
neuron
G protein
Na +
Figure 14–7. Transmitter release, action, and inactivation. Depolarization opens voltage- dependent Ca 2+ channels in the presynaptic
nerve terminal. (1) The influx of Ca 2+ during an action potential (AP) triggers (2) the exocytosis of small synaptic vesicles that
store neurotransmitter (NT) involved in fast neurotransmission. Released neurotransmitter interacts with receptors in the postsynaptic
membranes that either couple directly with ion channels (3) or act through second messengers, such as (4) GPCRs.
Neurotransmitter receptors in the presynaptic nerve terminal membrane (5) can inhibit or enhance subsequent exocytosis. Released
neurotransmitter is inactivated by reuptake into the nerve terminal by (6) a transport protein coupled to the Na + gradient, for example,
DA, NE, and GABA; by (7) degradation (ACh, peptides); or by (8) uptake and metabolism by glial cells (Glu). The synaptic vesicle
membrane is recycled by (9) clathrin- mediated endocytosis. Neuropeptides and proteins are stored in (10) larger, dense core
granules within the nerve terminal. These dense core granules are released from (11) sites distinct from active zones after repetitive
stimulation.
peptides) and reuptake into neurons by specific
transporters such as NET, SERT, and DAT (for NE,
5-HT, DA) (see Chapters 5, 8, and 13). Inhibitors of
NET, SERT, and DAT increase the dwell time and
thus the effect of those transmitters in the synaptic
cleft. Inhibitors of the uptake of NE and/or 5-HT are
used to treat depression and other behavioral disorders,
as described in Chapters 15 and 16.
Multiple transport proteins with selectivity for various transmitters
have been cloned (Figure 14–8). In contrast to the GPCRs
discussed earlier, these proteins have 12 hydrophobic membranespanning
domains. This means that both the amino and carboxy termini
are on the same, intracellular, side of the membrane. Like the
GPCRs, these transporters have sites for glycosylation on the cytoplasmic
side, primarily on the i2 loop, and sites for phosphorylation,
primarily on the amino and carboxy tails. Comparison of the
sequences of the transporters for NE and DA (Figure 14–8) reveals
striking conservation in the TM domains.
Neurohormones. The anterior and posterior pituitary secrete a variety
of hormones and releasing factors. Hypothalamic neurons affecting
the anterior pituitary release their hormones into the
hypothalamic–adenohypophyseal portal blood system, which delivers
them to the anterior pituitary, where they regulate the release of
trophic hormones (i.e., ACTH, FSH, GH, LH, prolactin) into the
blood. Other hypothalamic neurons project onto the posterior pituitary,
where they release their peptide contents, oxytocin and arginine
vasopression (anti- diuretic hormone, or ADH) into the systemic circulation
(Figure 14–9 and Chapters 25 and 38).
Cytochemical evidence indicates that the same substances
that are secreted as hormones from the posterior pituitary also mediate
transmission at these sites. Thus, the designation hormone relates