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

354
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D1 receptor family
D2 receptor family
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C
SECTION II
NEUROPHARMACOLOGY
receptors beyond the D1 and D2. This idea proved to be correct. The
D1 subfamily consists of the D 1
and D 5
receptor subtypes (initially
classified as D 1A
and D 1B
); both are GPCRs that couple to G s
to stimulate
cellular cyclic AMP production couple, but they differ in their
pharmacological profiles and primary amino acid sequences. The
D2 subfamily contains the D 2
, D 3
, and D 4
receptors. All reduce intracellular
cyclic AMP production by coupling to G i/o
proteins, but they
diverge in amino acid sequence and pharmacology. The D1 and D2
families can be further differentiated by their anatomical distribution
and by structural differences—the D1-like receptors have a relatively
long carboxyl terminus and a short third intracellular loop.
D 1
Receptors. The D 1
receptor is the most highly conserved
and the most highly expressed of the DA receptors.
The highest levels of D 1
receptor protein are found
within the CNS, particularly in the caudate putamen,
substantia nigra pars reticulata, nucleus accumbens,
hypothalamus, frontal cortex, and olfactory bulb. The
D 1
receptor is also located in the kidney, retina, and cardiovascular
system. Cloning reveals that the D 1
receptor
lacks introns and encodes a protein that is 446 amino
acids long in the human. The D 1
receptor couples primarily
to Gα s
, activating the cAMP-PKA pathway.
However, the neostriatum expresses the highest levels
of D 1
receptor, but does not express any detectable Gα s
protein. In this region of the brain, the D 1
receptor
appears to couple to G olf
to increase levels of cAMP and
its downstream effectors (for a review of dopaminergic
signaling, see Neve et al., 2004).
Reports of D 1
receptors coupling to G q
raised the possibility
that a third D1-like receptor might exist; there also are D 1
-D 2
receptor
heterodimers that couple to the G q
signaling cascade (Lee et al.,
C
cyclic AMP
cyclic AMP
K + currents
voltage-gated Ca 2+ currents
D 1 D 5 D 2 D 3 D 4
SNpr hypothalamus striatum n. accumbens PFC
frontal cortex
nucleus Acc
hypothalamus
striatum
NAc
SNpc
pituitary
PFC
SNpc
VTA
hypothalamus
amygdala
hippocampus
Figure 13–8. Distribution and characterization of DA receptors in the CNS.
2004). The presence of a functionally distinct heterodimer with a
unique dopaminergic pharmacology is a novel concept that could
shed new light on the actions of DA and drugs acting on the
dopaminergic system. In addition to forming protein complexes with
other DA receptors, the D 1
receptor has been shown to interact with
a variety of other proteins, including A 1
adenosine receptors, NMDA
receptors, Na + ,K + -ATPase, calnexin, and caveolin (for a review of
DA receptor protein-protein interactions, see Hazelwood et al.,
2009). The potential significance of these interactions with respect
to DA receptor function and potential pharmacotherapies has not
been fully realized.
D 2
Receptors. The D 2
receptor was the first dopamine
receptor to be cloned. It is expressed throughout the
brain, including the striatum, nucleus accumbens, olfactory
tubercule, prefrontal cortex, amygdala, ventral
tegmental area, hippocampus, hypothalamus, and substantia
nigra pars compacta. Unlike the D 1
receptor, the
D 2
receptor contains six introns and exists as either a
long or short splice variant. The D 2
short (D 2S
) receptor
is missing 29 amino acids in the third intracellular loop
that are present in the D 2
long (D 2L
) receptor variant.
The D 2L
receptor is the more predominantly expressed
variant in the brain and occurs primarily post-synaptically,
where it likely regulates impulse/signal propagation
(Usiello et al., 2000). The D 2S
variant is primarily
expressed pre-synaptically and likely acts to limit DA
release. The D 2S
and D 2L
receptors have similar pharmacological
properties and both function as autoreceptors,
inhibiting cAMP formation by coupling to G i/o
.
D 2
receptor signaling through G βγ
also regulates a variety of
cellular functions, including inwardly rectifying K + channels, N-type