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JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION
Vol. 24, No. 3, pp. 165–205, 2004
Dopamine Receptor Signaling
Kim A. Neve,1,* Jeremy K. Seamans,2 and Heather Trantham-Davidson2
1
Research Service, Veterans Affairs Medical Center and Department
of Behavioral Neuroscience, Oregon Health and Science University,
Portland, Oregon, USA
2
Medical University of South Carolina, Charleston, South Carolina, USA
ABSTRACT
The D1-like (D1, D5) and D2-like (D2, D3, D4) classes of dopamine receptors
each has shared signaling properties that contribute to the definition of the
receptor class, although some differences among subtypes within a class have
been identified. D1-like receptor signaling is mediated chiefly by the heterotrimeric G proteins Gs and Golf, which cause sequential activation of adenylate
cyclase, cylic AMP-dependent protein kinase, and the protein phosphatase-1
inhibitor DARPP-32. The increased phosphorylation that results from the
combined effects of activating cyclic AMP-dependent protein kinase and
inhibiting protein phosphatase 1 regulates the activity of many receptors,
enzymes, ion channels, and transcription factors. D1 or a novel D1-like receptor
also signals via phospholipase C-dependent and cyclic AMP-independent
mobilization of intracellular calcium. D2-like receptor signaling is mediated by
the heterotrimeric G proteins Gi and Go. These pertussis toxin-sensitive G
proteins regulate some effectors, such as adenylate cyclase, via their G subunits,
but regulate many more effectors such as ion channels, phospholipases, protein
kinases, and receptor tyrosine kinases as a result of the receptor-induced
*Correspondence: Kim A. Neve, Research Service, Veterans Affairs Medical Center and
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland,
OR, USA; E-mail: [email protected].
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DOI: 10.1081/LRST-200029981
Copyright & 2004 by Marcel Dekker, Inc.
1079-9893 (Print); 1532-4281 (Online)
www.dekker.com
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liberation of G subunits. In addition to interactions between dopamine
receptors and G proteins, other protein:protein interactions such as receptor
oligomerization or receptor interactions with scaffolding and signal-switching
proteins are critical for regulation of dopamine receptor signaling.
Key Words: Adenylate cyclase; G protein; Phospholipase; Glutamate; Protein
kinase; Extracellular signal-regulated kinase; Potassium channel; Sodium
channel; Calcium channel.
INTRODUCTION
Five subtypes of mammalian dopamine receptors are grouped into two classes,
with the D1-like receptor class composed of the D1 and D5 receptor subtypes, and
the D2-like receptor class composed of the D2, D3, and D4 receptor subtypes (1). At
the molecular level, most signaling properties are shared among all of the subtypes
within a class; similarity of signal transduction pathways is one of the criteria
by which subtypes are grouped into classes. In this review of dopamine receptor
signaling, we avoid repetition by discussing each class as a whole rather than treating
each subtype separately when little is known about subtype-specific properties,
making specific reference to a subtype primarily when there are data supporting a
unique property of that subtype.
All of the dopamine receptors are G protein-coupled receptors (GPCRs), whose
signaling is primarily mediated by interaction with and activation of heterotrimeric
GTP-binding proteins (G proteins). Members of this superfamily are also called
7-transmembrane receptors because they traverse the cell membrane seven times,
or serpentine receptors because of the manner in which they wind back and forth
across the membrane.
D1-LIKE RECEPTORS AND G PROTEINS
As receptors that stimulate adenylate cyclase, the D1-like receptors were
assumed to couple to the adenylate cyclase stimulatory G protein Gs. Because
Gs is ubiquitously expressed, the ability of D1-like receptors to stimulate
adenylate cyclase in virtually any cell line (2), together with physical and functional
coupling of both D1 and D5 receptors to Gs (3,4), strongly support the notion
that Gs mediates the D1-like receptor signaling in some tissues. In the
neostriatum, however, the brain region with the densest dopamine innervation
and the highest expression of the D1 receptor, expression of Gs is very low,
whereas Golf is abundantly expressed (5). The nucleus accumbens and olfactory
tubercle also express abundant Golf and little Gs (6). Golf is the heterotrimeric
G protein involved in olfaction, is very closely related to Gs (88% amino
acid homology), and also stimulates adenylate cyclase (7). Golf null mutant
mice exhibit little dopamine-stimulated adenylate cyclase; they also lack other
functional and behavioral responses to D1 receptor stimulation, including
cocaine or D1 agonist-induced locomotor activation and induction of c-fos
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expression in the neostriatum or nucleus accumbens, strongly suggesting that
Golf mediates D1 receptor signaling to adenylate cyclase in these basal ganglia
nuclei (5,8).
Less is known about the subunits that combine with Gs or Golf to mediate
D1-like receptor activation of adenylate cyclase. In human embryonic kidney (HEK)
293 cells, depletion of endogenous 7 subunit reduces D1 receptor stimulation of
adenylate cyclase, but not D5 receptor stimulation, indicating that 7 contributes
to this pathway for the former subtype (9). Depletion of 7 also decreases the
abundance of the 1 subunit, consistent with the formation of a 1 7 dimer; the
presence of Gs in HEK293 cells suggests that a G protein heterotrimer that mediates D1 receptor activation of adenylate cyclase is Gs1 7. Because 7 is abundantly
expressed in neostriatal medium spiny neurons (10), particularly in neurons that also
express D1 receptor mRNA (9), neostriatal D1 receptors may signal via a G protein
heterotrimer that includes both Golf and 7. In other brain regions, including dopamine target areas that express D1 and/or D5 receptors such as the cerebral cortex
and hippocampus where the expression of Golf is much lower than that of Gs (6), it
seems likely that Gs mediates D1 and D5 receptor signaling to adenylate cyclase.
Coupling of the D1 receptor to other heterotrimeric G proteins, such as Go and
Gq, and of the D5 receptor to Gz, has also been described (4,11). D1 receptor
interactions with Gq are particularly interesting in light of the possibility that D1 or
D1-like receptors activate phospholipase C, a phenomenon that will be discussed
in greater detail below.
D1-LIKE DOPAMINE RECEPTOR SIGNALING
D1-Like Receptor Stimulation of Adenylate Cyclase
The first biochemical evidence for a dopamine receptor was the identification
in 1972 of dopamine-stimulated adenylate cyclase activity and cyclic AMP
accumulation in the retina (12) and in rat neostriatum (13). Gs and,
presumably, Golf bind primarily to the C2 cytosolic domain of adenylate
cyclase, bringing the C1 and C2 domains together in a way that enhances
the catalytic efficiency of the enzyme (14). Adenylate cyclase catalyzes the
conversion of ATP to cyclic AMP, which binds to the regulatory subunits of
the protein kinase A (PKA) holoenzyme to disinhibit the catalytic subunits.
The selective concentration of the type 5 subtype of adenylate cyclase in the
neostriatum suggested that it mediates dopamine receptor signaling (15), a
hypothesis confirmed with the creation of adenylate cyclase 5 null mutant mice, in
which neostriatal D1 receptor-stimulated adenylate cyclase is markedly diminished
(16,17). Thus, in the rodent neostriatum the primary pathway for D1-like receptor
signaling is likely to be D1 receptor ! Golf/ 7 ! adenylate cyclase 5 ! PKA
(Figure 1). PKA phosphorylates a number of proteins involved in signal
transduction and regulation of gene expression (2,18).
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Figure 1. D1-like receptor signaling pathways. Stimulatory effects are indicated with a solid
line ending in an arrowhead, and inhibitory effects with a dashed line ending in a bar.
Intervening steps (e.g., MAPKKK ! MAPKK ! MAPK) are frequently omitted from the
figure for simplicity and ion channels are indicated generically, but are identified individually
in Fig. 2. AC5, adenylate cyclase type 5; CREB, cyclic AMP response element binding protein;
DARPP-32, dopamine-related phosphoprotein, 32 kDa; MAPK, mitogen-activated protein
kinase; NHE, Naþ/Hþ exchanger; PKA, protein kinase A; PKC, protein kinase C; PLC,
phospholipase C; PP1 or PP2A, protein phosphatase 1 or 2A.
D1-Like Receptor Regulation of PKA Substrates
PKA Substrates—DARPP32
DARPP-32 (dopamine and cyclic AMP-regulated phosphoprotein, 32 kDa)
is a neostriatum-enriched bifunctional signaling protein that inhibits protein phosphatase 1 (PP1) when phosphorylated on Thr34 by PKA or several other kinases
(19,20) and inhibits PKA when phosphorylated on Thr75 by cyclin-dependent
kinase 5 (21). Because Thr75 is dephosphorylated by the PKA-stimulated protein
phosphatase-2A (22), D1-like receptor signaling is amplified by both positive
feedback and feedforward loops. D1 receptor stimulation simultaneously activates
PKA by stimulating the production of cyclic AMP and disinhibits PKA
by phosphorylation-dependent activation of protein phosphatase-2A and Thr75
dephosphorylation of DARPP-32. At the same time, D1-like receptor activation of
PKA not only stimulates PKA-catalyzed phosphorylation of numerous substrates
including some described below but also prevents PP1-catalyzed dephosphorylation
of many of the same phosphoproteins by phosphorylating DARPP-32 on Thr34.
Studies with DARPP-32 null mutant mice have shown that DARPP-32 contributes
to acute D1 receptor-mediated responses, both at the cellular and behavioral levels
(20). Consistent with a signal amplification role for DARPP-32, many deficits
associated with genetic deletion of the PP1 inhibitor are observed only at low doses
of dopamine receptor agonist (23–25).
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PKA Substrates—Ion Channels
D1-like receptor activation of PKA increases the phosphorylation of numerous
voltage- and ligand-gated ion channels by various combinations of direct PKAcatalyzed phosphorylation of channel subunits and DARPP-32-mediated inhibition
of PP1. For example, there are at least five potential PKA phosphorylation sites in
the LI-II region of the pore-forming -subunit of voltage-gated Naþ channels
(26), and activation of DARPP-32 also decreases PP1-catalyzed dephosphorylation
at Ser573. Enhanced phosphorylation at Ser573 decreases Naþ currents through a
decrease in the open probability of the channel (26–30). D1 receptor stimulation of
PKA also decreases Kþ currents through several types of inwardly rectifying
channels, increases L-type, and decreases N and P/Q type Ca2þ channel activity,
increases NMDA receptor activity via phosphorylation of the NR1 subunit, enhances
AMPA currents, and modulates GABA currents. Because D1-like receptor regulation of ion channels often involves multiple, incompletely defined signaling
pathways in addition to PKA, this topic is discussed in greater detail below.
PKA Substrates—CREB
D1 receptor stimulation induces the expression of a number of transcription
factors (31,32), at least some of which are dependent on initial activation of the
transcription factor cyclic AMP response element-binding protein (CREB) (31,33).
D1 receptor activation of CREB involves PKA-dependent CREB phosphorylation of
Ser133, which permits binding of CREB to CREB-binding protein and transcriptional activation of genes with cyclic AMP response elements (34). D1 receptor
stimulation may also increase Ser133-phosphorylated CREB via activation of
extracellular signal-regulated kinase (ERK) (35). Phosphorylation of CREB is also
regulated by Ca2þ, so the transcription factor is likely to be an important site
of integration for signals from dopamine and N-methyl-D-aspartate (NMDA)
glutamate receptors (Figure 1). CREB-mediated changes in gene expression are
important in synaptic plasticity and probably contribute to synaptic rearrangements
that underlie the persistence of drug addiction (36).
D1-Like Receptor Stimulation of Phospholipase C
One finding that is difficult to reconcile with a model of D1 receptor signaling
that includes a central role for a cyclic AMP/PKA cascade is that a null mutation of
adenylate cyclase 5 enhances D1 agonist-stimulated locomoter activity even though
D1 receptor stimulation of adenylate cyclase activity is almost abolished (16,17).
Mice with genetic deletion of adenylate cyclase 5 have altered abundance of several
proteins involved in dopamine receptor signaling and also disrupted D2 receptor
signaling, making interpretation of behavioral effects complicated, but one possible explanation is that a cyclic AMP-independent signaling pathway mediates
D1 receptor locomotor activation, and perhaps other behavioral effects of D1
receptor stimulation. One such alternative pathway for D1-like receptor signaling
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is phospholipase C-mediated mobilization of intracellular calcium (37). There are at
least two distinct potential mechanisms for D1-like receptor activation of phospholipase C. Bergson and colleagues demonstrated that heterologously expressed D1
and D5 dopamine receptors, when co-expressed with calcyon, stimulate the release
of calcium from intracellular stores following priming of the cells with a Gqcoupled receptor agonist (38). The effect of calcyon is dependent on its binding to
the C terminus of the D1 receptor. Endogenous D1-like receptors in neocortical
or hippocampal neurons, but not neostriatal neurons, display a similar primingdependent ability to mobilize calcium (39). Whether this involves calcyon-dependent
enhancement of coupling to Gq and direct activation of phospholipase C is
unknown, although the lack of effect of cyclic AMP analogues indicates that it is not
mediated by PKA.
A second potential cyclic AMP-independent mechanism for D1-like receptor
signaling invokes a novel SCH23390-binding receptor that is linked to phospholipase
C via Gq (40,41). The regional distribution and pharmacological profile of D1-like
receptor-stimulated phospholipase C differ from both D1 and D5 receptors. Some
compounds efficacious for stimulating adenylate cyclase are weak agonists or
antagonists at the phospholipase C-coupled receptor, whereas the drug SKF83959
has little efficacy for adenylate cyclase but is one of the most potent and efficacious
agonists known to stimulate the phospholipase C-coupled receptor (42,43). D1-like
receptor-stimulated phospholipase C is most abundant in the amygdala and hippocampus (40); it is of interest that the amygdala has a relatively dense dopaminergic
innervation and abundant D1 receptors but little or no D1 receptor-stimulated
adenylate cyclase (44). D1-like receptors are also functionally and physically coupled
to Gq, with the distribution of Gq-coupled receptors roughly paralleling that
of D1-like receptor-stimulated phospholipase C (4,41,45). This putative D1-like
Gq-coupled receptor does not react with a D1 receptor antibody (4,45) and is not
a product of the drd1 gene because D1-like receptor-stimulated phospholipase C is
spared in D1 receptor null mutant mice (46); indeed, the existence of a genetically
distinct phospholipase C-coupled D1-like receptor has been used to explain the conservation of D1 agonist-stimulated behaviors in D1 null mutant mice (47), although
the mixed genetic background of the mice also affected the observed phenotype (48).
A major inconsistency in this otherwise intriguing hypothesis is that [3H]SCH23390
binding sites are undetectable in most brain regions of the D1 null mutant mouse
(49), including in amygdala where stimulation of phospholipase C is most robust,
a finding difficult to reconcile with numerous reports that SCH23390 is a potent
antagonist ligand of the Gq- and phospholipase C-coupled D1-like receptor.
D1-Like Receptor Regulation of Ion Channels
D1-Like Receptor Regulation of Kþ Channels
Activation of D1-like or D2-like receptors has opposing effects on Kþ currents
in most cells. In general, D1-like receptors attenuate these currents via stimulation
of the PKA-DARPP-32 signaling cascade, whereas the D2-like receptors enhance
them via inhibition of that pathway as well as by release of G subunits (Figure 2).
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Figure 2. Regulation of ion channels by D1-like (top) and D2-like (bottom) dopamine
receptors. Stimulatory (solid line with arrowhead) or inhibitory (dashed line with bar) effects
of dopamine receptors on GABA receptors (GABA), NMDA glutamate receptors (NMDA),
AMPA glutamate receptors (AMPA), L- and N,P,Q-type Ca2þ channels, persistent (P) and
transient (T) Naþ channels, G protein-regulated inwardly rectifying Kþ channels (GIRK), and
voltage-gated Kþ channels (VGKþC) are schematically depicted, as well as whether the effect
is thought to be mediated by protein kinase A (PKA), protein kinase C (PKC), G protein subunits (G), or inhibition of the cyclic AMP/PKA pathway (#PKA).
We focus here on voltage-gated (IA/IAf, ID/IAs/IKS, IK/IKSS) and inwardly rectifying
potassium currents that primarily act to regulate firing rate, stabilize membrane
potential, and integrate subthreshold inputs.
The family of outwardly rectifying voltage-gated Kþ channels in neocortical
neurons has been separated into three different components based on their inactivation kinetics (IAf, IKS, IKSS). The terminology differs among studies so that it can
sometimes be difficult to understand exactly which component is being measured.
Here, we have separated the components according to the criteria developed by
Foehring and Surmeier (50). IAf is the rapidly inactivating component of this current
and can also be referred to as the fast A-type current (IA) because it shows fast
inactivation kinetics (around 12 msec at 10 mV). IKS, also referred to as ID, IAs, or
the slow A-type current, is the slowly inactivating component of this voltage-gated
Kþ current and has an inactivation time constant of 293 msec at 10 mV. Finally,
IKSS, also referred to as IK, is the very slowly inactivating component, with an
inactivation time constant between 2 and 20 sec.
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In medium spiny neurons of the striatum and nucleus accumbens, the IA type
current is important for regulation of firing rate. This current has at least two
components that are activated depending on the membrane potential of the cell.
The fast component (IAf) is activated at more depolarized membrane potentials and
does not appear to be modulated by D1 receptor stimulation. However, at more
hyperpolarized membrane potentials, such as during the down state, the slower
component of this current (IKS/IAs/ID) is available. In the nucleus accumbens,
combined activation of D1 and D2 receptors increases neuronal firing rate by
inhibition of ID. The precise signaling mechanism used by each receptor has not
been worked out, but this response is dependent on activation of cAMP/PKA and
on D2-like receptor-mediated liberation of G. These pathways converge on the
A-type Kþ current to attenuate the outward flow of Kþ ions (51). These authors
speculated that D1-Gs/Golf and D2-G are acting cooperatively to increase
adenylate cyclase and PKA activity and produce the observed changes in potassium
currents (52,53). This is one of several mechanisms that may contribute to D1/D2
receptor synergism (54).
D1-like suppression of Kþ currents in the prefrontal cortex has important effects
on the excitability of both interneurons and pyramidal cells; elucidating these effects
is important for understanding how dopamine will modulate these cortical activity
states. D1 stimulation increases evoked GABA release from interneurons via an
increase in their excitability. This increase in excitability appears to be due to D1PKA-stimulated decrease of Kþ currents in one class of interneurons, the so-called
fast-spiking parvalbumin positive cells (55). Dopamine via D1-like receptors
suppresses an inwardly rectifying Kþ current, a Kþ-dependent leak current,
and the slowly inactivating membrane outward rectification in prefrontal cortex
fast-spiking interneurons. Collectively, these D1-mediated modulations of Kþ
currents act to depolarize and increase the evoked output of a specific subclass
of interneurons. Pyramidal cell excitability is regulated by D1 receptor- and
PKA-mediated decreases in Kþ currents in a similar manner. D1 reduction of
the voltage-gated, slowly inactivating Kþ current (ID) in pyramidal cells results in
a stronger effect of subthreshold inputs because a decrease in IK will lesson opposition to depolarization and latency to first spike (56,57). These D1 effects on
pyramidal cells may be mediated through elevation of PKA and increased phosphorylation of DARPP-32. In contrast, the inwardly rectifying Kþ channels may be
modulated in a slightly different manner from other Kþ currents. It appears that D1like receptor stimulation inhibits voltage-gated Kþ channels as a result of direct
binding of cyclic AMP to the channel, thus increasing cell excitability (58,59). Overall,
in the prefrontal cortex, dopamine acts via D1-like receptors to increase the excitability of both pyramidal neurons and fast-spiking interneurons through inhibition
of several Kþ currents.
D1-Like Receptor Regulation of Ca2þ Channels
Dopamine modulates high-voltage-activated Ca2þ currents in several types
of vertebrate and invertebrate neurons in vitro (60–63). D1 receptor stimulation
increases L-type and decreases N, P/Q-type Ca2þ channel conductances in most
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brain areas (Figure 2). In cortical cells L-type channels are associated with the
somatic region of cells and exert a powerful effect on signal integration. N- and P/Qtype channel activation produces Ca2þ spikes mainly within more distal dendritic
regions of somotosensory (64) but not prefrontal cortical neurons (65).
In striatum, D1-like receptor-mediated decreases in N- and P/Q-type conductances inhibit spike-induced Ca2þ influx, whereas increases in L-type currents lead to
depolarization (62). This effect on L-type channels becomes even more pronounced
in conjunction with the D1-mediated decrease in Kþ currents discussed above and
the increase in NMDA current. D1 receptor-stimulated increases in L-type conductances, which are very slow to inactivate, might help to stabilize the prolonged
depolarizations (63).
D1-like receptors decrease N- and P/Q-type Ca2þ channels via activation of
PKA and DARPP-32 (62). The 1 subunit of these channels contains phosphorylation sites for PKA, but phosphorylation of these sites by PKA activates the
channels (66). Surmeier et al. (62) speculate that the D1-mediated decrease in N- and
P/Q-type currents is therefore due not to a direct phosphorylation of the channel
by PKA, but rather to a transient increase in PP1-catalyzed dephosphorylation
caused by PKA-dependent phosphorylation of PP1-targeting proteins. This effect
would be rapidly reversed by comcomitant PKA phosphorylation of DARPP-32,
which attenuates PP1 dephosphorylation of the channel (67). According to this
hypothesis, however, D1-like receptor inhibition of these channels should be
prolonged in DARPP-32 null mutant mice; in contrast, D1 agonist-induced
inhibition of the channels is decreased in DARPP-32 null mutant mice (23).
D1-like receptor effects on Ca2þ channels in the prefrontal cortex are similar
to those in the striatum, although the pathways have not been completely worked
out, and appear to serve as a gain control mechanism to amplify somatic inputs via
increases in L-type Ca2þ currents and attenuate dendritic inputs via decreases in
N- and P/Q-type currents (56,58). Direct D1-like receptor stimulation induces
a complex modulation of Ca2þ potentials in prefrontal cortex neurons. D1-like
agonists suppress full Ca2þ spikes via a Ca2þ- and PKC-dependent pathway (56,68).
In contrast, subthreshold depolarizations produced by L-type Ca2þ channels (65) are
augmented transiently (7 min) by D1-like receptor agonists (68), an effect that
is blocked by PKA inhibitors. In this way, D1-like receptor stimulation activates
PKA to potentiate subthreshold L-type Ca2þ currents, yet it acts via PKC to suppress large amplitude Ca2þ spikes, thereby tuning Ca2þ currents to have the greatest
activation in the voltage range necessary to produce spikes. Coupled with the
D1 receptor-mediated increase in INap (see below) and decrease in Kþ currents, D1
receptor activation greatly prolongs the output of prefrontal pyramidal neurons.
D1-Like Receptor Regulation of Naþ Channels
Voltage-gated Naþ channels are important for determining threshold for action
potential initiation, the duration and frequency of firing, EPSP amplification, and
resonance properties of neurons (69–71). D1-like receptor stimulation exerts a
powerful influence over cellular activity through manipulation of the phosphory-
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lation state of these channels. D1 effects may differ depending on the specific type
of Naþ channel activated and the brain area in which DA is acting.
In the neostriatum and hippocampus, down-regulation of transient Naþ currents
by a D1-PKA-DARPP-32 pathway that increases phosphorylation of Ser573 of
the Naþ channel -subunit decreases excitability of cells and increases rheobase
current by increasing the action potential threshold to more depolarized levels
(20,23,26,27,72–74). The functional effect of this modulation is to decrease the
output of these neurons, but the modulation may be state dependent. Neostriatal
cells have rhythmic oscillations in membrane potential (up- and downstates), and
it appears that D1 receptor activation creates more selectivity for depolarizing inputs
that will evoke an upstate because it opposes the activation of Naþ currents (27).
As a result, depolarizing inputs must be stronger to evoke a postsynaptic response
and thus cells are more selective about which inputs drive upstates. The D1-PKADARPP-32 modulation of striatal Naþ channels, therefore, tends to counteract the
effectiveness of depolarizing inputs that drive these neurons into upstates.
In neocortical neurons, one type of voltage-gated Naþ channel carries two
þ
Na currents by virtue of its ability to switch between gating modes (75–77). The
fast-gating mode is similar to the transient Naþ current discussed above, whereas
the other current is a slowly inactivating or persistent Naþ current (INaP) (78,79).
Individual Naþ channels can exhibit this persistent gating mode, but only a small
fraction of the channels are in this gating mode at any time.
As in neostriatal neurons, D1-like receptor stimulation of PKA decreases
transient Naþ currents in neocortical pyramidal cells (80). On the other hand,
D1-like receptors may enhance INaP (56,81), decrease it (82), or have no effect (80).
The D1-mediated modulation reported by Gorelova and Yang (81) occurs at
subthreshold membrane potentials by shifting INaP activation to more negative
membrane potentials and slowing its inactivation (56,81). Rather than being mediated by PKA, the D1 receptor effect on INaP in intact prefrontal cortical neurons
from brain slices is mediated by PKC (81). Maurice et al. (80), who observed no
effect of D1-like receptor activation on INaP in acutely dissociated prefrontal cortical
neurons, proposed that the Nav1.6 -subunit, which lacks the phosphorylated
residue Ser573, contributes disproportionately to the persistent current, whereas
the transient current is attributable to the PKA-sensitive Nav1.1/1.2 channel,
again supporting the notion that modulation of the persistent current is not through
PKA (Figure 2).
D1-Like Receptor Regulation of Glutamate Receptors
D1-like receptors interact with glutamate receptors at multiple levels, including
signal integration by CREB and PKA-dependent phosphorylation of the glutamate receptors. D1-like receptors increase NMDA receptor-mediated responses
in neostriatal (83–86), hippocampal (87), and cortical neurons (88–91) and enhance
phosphorylation of the NMDA-NR1 subunit. DARPP-32 is required for D1
receptor-stimulated phosphorylation of NR1 and for the increased NMDA-evoked
responses (20,86,92). A contribution of D1-like receptor activation of L-type Ca2þ
channels and protein kinase C has also been described (93,94), whereas other studies
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have focused on the role of PKA (95). PKA/DARPP-32 may enhance NMDA
receptor function by a complex combination of mechanisms including direct phosphorylation of NR1 by PKA, DARPP-32-mediated inhibition of dephosphorylation
of NR1, and depolarization via DARPP-32-mediated activation of L-type Ca2þ
channels (20,91).
An additional consideration is that D1 effects may be state dependent. If the
target cell is in a depolarized state, then D1 receptor stimulation increases NMDA
currents, but if it is in a hyperpolarized state when dopamine is applied, then D1-like
receptor activation decreases NMDA receptor currents (27,96,97). A positive feedback situation may exist in that NMDA receptor activation in depolarized cells may
benefit from the simultaneous D1 receptor-mediated modulation of INap, Ca2þ
channels, and NMDA receptors; greater depolarization is produced, these voltagedependent currents become larger, thus evoking more depolarization, thereby
enhancing the subtle actions of dopamine.
Dopamine appears to exert opposing effects on AMPA currents via activation of
D1 and D2 receptors. Both receptor subtypes can activate kinases that target specific
residues on AMPA receptors, but as for NMDA receptors, experiments to elucidate
signaling pathways regulating these voltage-dependent receptors are complicated by
the necessity to exclude dopamine receptor effects on other ion currents.
D1 receptor activation may have variable effects on AMPA currents in the
striatum, with a small effect to enhance the currents, and a larger effect to stabilize
them by delaying AMPA receptor current ‘‘rundown’’ (98–100). The stabilization
may be mediated by both PKA-catalyzed phosphorylation of the GluR1 subunit
at Ser845 and DARPP-32 inhibition of PP1-catalyzed dephosphorylation of the
residue (100–103), whereas enhanced amplitude may reflect D1-like receptor
activation of L-type Ca2þ channels (62,93,99), also mediated by PKA/DARPP-32.
Thus, D1 receptor-mediated enhancement of AMPA currents would depend on the
co-presence of the Ca2þ channels, perhaps accounting for some variability in results.
To complicate matters further, there is some debate about whether the effects of
D1 stimulation occur pre- or postsynaptically. In prefrontal cortex, D1 receptor
stimulation attenuates AMPA currents by decreasing the probability of glutamate
release from presynaptic cells. This implies that rather than a direct effect of
D1 receptor activation on AMPA receptors, decreased synaptic glutamate levels
manifest themselves as decreases in AMPA currents (89). Later work supported this
idea by removing the presynaptic component of this response. When only the
postsynaptic effect is examined, then D1-like receptor stimulation slightly increases
AMPA currents via a Ca2þ-dependent mechanism (104).
D1-like receptor stimulation also enhances the trafficking of NMDA receptors
and the GluR1 subunit of AMPA receptors to the membrane in neurons (105,106).
Enhanced trafficking of GluR1 is mimicked by forskolin-induced activation
of adenylate cyclase (106), whereas that of NMDA receptors is independent of
DARPP-32 but requires the Src-family protein tyrosine kinase Fyn (107). Finally, a
direct protein-protein interaction between the C termini of the D1 receptor and the
NR1-1a and NR2A NMDA receptor subunits mediates reciprocal regulation of
receptor function and trafficking (108–110). In particular, this physical interaction
permits D1 receptor inhibition of NMDA receptor currents (108).
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D1-Like Receptor Regulation of GABA Receptors
Dopamine exerts varied effects on GABAA currents depending on the brain
area and cell type being examined. One reason for these various effects could be
the subunit composition of the GABA receptors located in these different areas,
because different isoforms of -, -, and -subunits are differentially affected by
protein kinases. D1-like receptor stimulation decreases GABA receptor activation in
medium spiny neurons from neostriatum and nucleus accumbens (24,111), an effect
associated with phosphorylation of 1/3 subunits and activation of PKA/DARPP32 (24). In large cholinergic interneurons of the neostriatum, D1-like agonists have
been reported to have no effect on GABA receptor IPSPs (112) or to enhance the
activity of a subpopulation of zinc-sensitive GABAA receptors via the D5 receptor,
PKA, and PP1 (113).
As for the D1 and NMDA receptors, mutually inhibitory modulation
between D5 and GABAA receptors results from a protein-protein interaction
between the D5 receptor and the 2 subunit of the GABAA receptor (114). These
direct interactions between D1-like and ion channel-coupled receptors may represent G protein-independent mechanisms of signaling, although it is also possible
that G protein activation is required for formation of the multiprotein signaling
complex.
D1-Like Receptor Regulation of Other Signaling Pathways
Inhibition of Naþ-,Kþ-ATPase
D1-like receptors inhibit Naþ-,Kþ-ATPase in many peripheral and neural
tissues (115,116). Multiple mechanisms mediate this effect. Activation of DARPP-32
plays a key role in both renal tubule cells (117), where inhibition of Naþ-,
Kþ-ATPase contributes to D1 receptor-stimulated natriuresis and diuresis, and
neostriatal neurons (23). Phospholipase C-dependent mechanisms have also been
described (118,119), and D1-like receptor inhibition of Naþ/Hþ exchange would
also be expected to inhibit Naþ-,Kþ-ATPase activity by decreasing the intracellular
concentration of Naþ (for an extensive review, see 115).
Activation of Mitogen-Activated Protein Kinases
Several reports describe D1-like receptor activation of mitogen-activated protein
(MAP) kinases, including ERK (35,120), p38 MAP kinase, and c-jun amino-terminal
kinase (121). Regulation of the latter two MAP kinase pathways is mediated by PKA,
whereas D1-like receptor activation of ERK may be partially independent of PKA
or cyclic AMP. One possible PKA-independent but cyclic AMP-dependent mechanism for activation of ERK by the D1 receptor is activation of the Rap GTPase
(122) by the cyclic AMP-activated guanine nucleotide-exchange factor Epac (123).
Dopamine Receptor Signaling
177
D2-LIKE RECEPTORS AND G PROTEINS
D2-like receptor signaling is mediated primarily by activation of the heterotrimeric G proteins Gi/o, a class of G proteins inactivated by pertussis toxincatalyzed ADP-ribosylation (124,125). For the D2 receptor, the possibility that
the alternatively spliced insert in the third cytoplasmic loop of D2L might
influence G protein interactions and result in differential G protein selection by
D2S and D2L has meant that analyses of G protein selection often focus on
comparisons between the two isoforms. There is considerable disagreement in the
literature concerning which G proteins interact with D2S and D2L (126,127). It
seems likely that both receptor isoforms are inherently able to activate multiple
Gi/o subtypes, including Gi2, Gi3, and Go (128,129), but that interactions with
particular G proteins are restricted in a cell-type dependent manner due to
compartmentalization or the availability of appropriate effectors and scaffolding
proteins. D2S and D2L can also activate the pertussis toxin-insensitive G protein
Gz (130,131). This interaction could explain some reports of pertussis toxininsensitive signaling by the D2 receptor (132–134). Nevertheless, accumulating
evidence from a variety of approaches has identified Go as the Gi/o subtype that is
most robustly activated by D2L (135–137) and by D2S (138–140) and, furthermore,
the G protein subtype that is predominantly coupled to D2-like receptors in mouse
brain (141).
The human D4 receptor is similar to D2 in that it activates multiple
pertussis toxin-sensitive G proteins, including Gi2, Gi3, and Go (142,143).
The rat D4 receptor has been reported to couple preferentially to Gz (131) and
to the pertussis toxin-sensitive transducin subtype, Gt2 (144). Work by several
groups has identified Go as being activated by the D3 receptor and mediating
D3 signaling, with some evidence for D3 receptor signaling via Gz and Gq/11
(131,142,145,146). An example of the importance of cell-type specific factors in the
selective activation of G proteins by GPCRs is that the D3 receptor couples
more efficiently to Go in SH-SY5Y cells than in HEK293 cells, despite the
abundance of that G protein subtype in both cell lines (146). Zaworski et al. (146)
suggest that the additional presence in SH-SY5Y cells of effectors regulated by
the D3 receptor contributes to the efficient activation of Go by the D3 receptor
in those cells, a hypothesis consistent with other work showing that receptors
form complexes with effectors and that G proteins participate in complex
formation (147).
An unusual feature of the D3 receptor is that it binds agonists with a high
affinity that is relatively insensitive to GTP (126). The affinity of GPCRs for agonists
is typically reduced by GTP, reflecting GTP-induced destabilization of the agonistreceptor-G protein ternary complex. The insensitivity of the D3 receptor to
GTP could reflect GTP-resistant coupling to G proteins or a receptor structure
that is constrained in a comformation with high affinity for agonists regardless of
interactions with G proteins; interesting work by Leysen and colleagues expressing the D3 receptor in E. coli, and thus in the absence of endogenous G proteins
with which the receptor can interact, indicates that the latter explanation is more
likely (148).
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D2-LIKE DOPAMINE RECEPTOR SIGNALING
D2-Like Receptor Signaling via Gai/o—Inhibition of Adenylate Cyclase
The first signaling pathway identified for D2-like receptors was inhibition of
cyclic AMP accumulation (149,150). As for D1 receptor stimulation of adenylate
cyclase, genetic deletion of adenylate cyclase 5 abolishes D2 receptor-mediated
inhibition of adenylate cyclase in the mouse neostriatum. That this null mutation
also eliminates the locomotor inhibitory effects of D2 receptor-blocking antipsychotic drugs shows the behavioral significance of this signaling pathway (16). The
lack of responsiveness to antipsychotic drugs is a phenotype also seen in D2 receptor
(151) and DARPP-32 (20) null mutant mice, further indicating that this signaling
pathway contributes to D2 receptor-stimulated locomotor activity. D2 and D4
receptors inhibit adenylate cyclase activity in a variety of tissues and cell lines
(2,152). Inhibition of adenylate cyclase by the D3 receptor is weaker and often
undetectable although it is of interest that the D3 receptor robustly inhibits adenylate cyclase type 5 (153,154), in contrast to several other adenylate cyclase subtypes
including the closely related type 6. On the other hand, co-expression of D2 and D3
receptors in COS-7 cells with adenylate cyclase 6 substantially increases the potency
of D2-like receptor agonists for inhibition of cyclic AMP accumulation, suggesting
that the D2/D3 heteromer has increased potency for agonists and/or couples more
efficiently to adenylate cyclase 6 (154,155).
D2-like receptor inhibition of adenylate cyclase is presumed to be mediated
by Gi/o, because adenylate cyclase 5 is directly inhibited by Gi and is insensitive
to G (156). Gi binds primarily to the C1 cytosolic domain of Gi-inhibited forms
of adenylate cyclase and reduces C1/C2 domain interaction (157). One inconsistency
is that adenylate cyclase 5 expressed in insect Sf9 cells is insensitive to purified
Go (156), whereas work cited above supports a prominent D2 ! Go ! adenylate
cyclase 5 signaling path.
D2 receptor signaling via inhibition of adenylate cyclase would be expected
to act in opposition to agents that stimulate adenylate cyclase, decreasing the
phosphorylation of PKA substrates (Figure 3). For example, stimulation of D2-like
receptors decreases PKA-stimulated phosphorylation of DARPP-32 at Thr34 and
increases phosphorylation at Thr75 (22,158). Both of these effects may be at least
partially mediated by Gi-dependent inhibition of cyclic AMP, although for Thr34,
the lack of effect of quinpirole in Ca2þ-free medium is difficult to reconcile with a
major role for adenylate cyclase inhibition; calcium-dependent stimulation of
calcineurin (protein phosphatase 2B) also contributes to D2 receptor dephosphoryation of Thr34 (158). It is of interest that the opposing effects of D1 and D2
receptors on DARPP-32 both lead to inhibition of the Naþ,Kþ-ATPase in
neostriatal neurons (159). Another response potentially mediated by D2-like
receptor inhibition of adenylate cyclase is autoreceptor suppression of tyrosine
hydroxylase activity. Stimulation of D2-like synthesis-inhibiting autoreceptors
reverses PKA-dependent phosphorylation of tyrosine hydroxylase at Ser40 and
activation of the enzyme (160). Although it is reasonable to speculate that inhibition
of adenylate cyclase contributes to this response, a role for other mechanisms, such
as calcium-stimulated protein phosphatases, has not been excluded. Inhibition of
Dopamine Receptor Signaling
179
Figure 3. D2-like receptor signaling pathways. Stimulatory effects are indicated with a solid
line ending in an arrowhead, and inhibitory effects with a dashed line ending with a bar.
Intervening steps (e.g., MAPKKK ! MAPKK ! MAPK, or the multiple possible steps
between G and RTK) are frequently omitted from the figure for simplicity. See Fig. 2 for
more specific description of ion channels. AA, arachidonic acid; AC2 or AC5, adenylate
cyclase type 2 or 5; CREB, cyclic AMP response element-binding protein; DARPP-32,
dopamine- and cyclic AMP-regulated phosphoprotein, 32 kDa; MAPK, mitogen-activated
protein kinase; NHE, Naþ/Hþ exchanger; PA, phosphatidic acid; PC, phosphatidylcholine;
PI3K, phosphatidylinositol 3-kinase; PKA, protein kinase A; PKC, protein kinase C; PLA2,
phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; PP1 or PP2A, protein
phosphatase 1 or 2A; RTK, receptor tyrosine kinase.
adenylate cyclase is also likely to be the mechanism of D4 receptor-induced
inhibition of GABA currents in rat globus pallidus, perhaps by decreasing PKAdependent phosphorylation of the 3 subunit of the GABAA receptor (161), and the
proximal mechanism of D4 receptor-induced inhibition of NMDA receptor currents
in rat prefrontal cortex, for which the complete pathway is apparently disinhibition
of PP1, dephosphorylation of autophosphorylated calcium-, calmodulin-dependent
kinase II thus reducing its calcium-independent kinase activity, and decreased
phosphorylation of the NR1 subunit of the NMDA receptor which in turn decreases
NMDA receptor expression in the plasma membrane (162). On the other hand,
inhibition of NMDA receptor transmission by the D4 receptor in rat hippocampus
apparently involves platelet-derived growth factor receptor-dependent mobilization
of calcium rather than inhibition of PKA-dependent phosphorylation (163).
D2-Like Receptor Signaling Mediated by G Protein Subunits
As is typical of Gi/o-coupled receptors, D2-like receptors modulate many
signaling pathways in addition to adenylate cyclase, including phospholipases, ion
channels, MAP kinases, and the Naþ/Hþ exchanger (2). Many of these pathways
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Neve, Seamans, and Trantham-Davidson
are regulated by G protein subunits that are released by receptor activation
of Gi/o proteins (Figure 3).
G-Stimulated Adenylate Cyclase
G has a permissive effect on adenylate cyclase 2 and 4, so that the stimulatory
effect of other activators, including Gs and protein kinase C, is enhanced in the
presence of free G (52,53,156). G binds to residues in several cytosolic domains
of adenylate cyclase 2, with stimulation primarily due to binding to the less conserved region of cytosolic loop 1, C1b (164,165). This G-mediated stimulatory effect
is primarily observed for Gi/o-coupled receptors, perhaps because activation of
only this relatively abundant class of G proteins liberates a sufficient concentration of G subunits. D2 and D4 receptors markedly increase the activity of
adenylate cyclase 2, whereas the D3 receptor has little or no effect (53,153). D2-like
receptor activation of G-stimulated adenylate cyclase response has only been
observed by using heterologously expressed receptors and adenylate cyclase. It is
not known if it contributes to D2-like receptor signaling in neurons, although it has
been speculated that G-stimulated adenylate cyclase contributes to synergistic
activation of spike firing in nucleus accumbens neurons by D1-like and D2-like
receptors (51).
G-Stimulated Kþ Channels
D2 stimulation exerts a powerful influence over Kþ currents likely via
dissociation of G subunits rather than by Gi-dependent inhibition of adenylate
cyclase activity. Unlike the generally excitatory effect of D1 receptor stimulation,
D2 stimulation decreases cell excitability by increasing Kþ currents in most brain
areas (Figure 2).
All of the D2-like receptors activate a G protein-regulated inwardly rectifying
potassium channel (GIRK or Kir3), a channel that carries one of several potassium
currents modulated by dopamine in midbrain dopamine neurons (166,167), and
neostriatal D2 receptor-expressing neurons (168), with activation presumably via
G (169–171). The D3 receptor is approximately as efficient as the D2L receptor
at coupling to homomeric GIRK2 (172), the GIRK subtype predominantly
expressed by dopamine neurons in the rat ventral mesencephalon (173,174), and
regulation of GIRK channels contributes to inhibition of secretion by the D3
receptor heterologously expressed in AtT-20 mouse pituitary cells (175). D2 and
D4 receptors both co-precipitate with GIRK channels in a heterologous
expression system, and the rat neostriatal D2 receptor co-precipitates with
GIRK2, suggesting the existence of a stable complex that forms during receptor/
channel biosynthesis (147). The formation of large multiprotein complexes that
include GPCRs and their effectors may be a general characteristic of GPCR
signaling (176). Evidence that dopamine release-regulating autoreceptors are
coupled to potassium channels (177) rather than to inhibition of adenylate
cyclase (178), together with the robust regulation of GIRK currents by D2
Dopamine Receptor Signaling
181
receptors in substantia nigra dopamine neurons (179), suggests that D2 receptor
activation of GIRK currents contributes to D2 autoreceptor inhibition of dopamine
release and dopamine neuronal activity. The hyperactivity and facilitation of D1
receptor signaling observed in GIRK2 null mutant mice (180) is also consistent with
a loss of inhibitory autoreceptor function.
The effect of D2 stimulation on voltage-gated outward potassium currents
appears to depend on the brain area being examined. Medium spiny neurons in
the striatum show an increase in the amplitude of the slowly inactivated Kþ current
(ID) in the presence of D2 agonists (181), but pyramidal neurons of the cortex show
no effect of D2 stimulation on this same current (57). More work is needed to
understand the mechanism by which D2 receptors exert their effects on voltage-gated
Kþ channels.
G-Mediated Regulation of Ca2þ Channels
All D2-like receptors decrease the activity L, N, and P/Q-type channels via
pertussis toxin-sensitive G proteins (128,182–185). D2 receptors in neostriatal large
aspiny (cholinergic) interneurons inhibit N-type Ca2þ channels by a membranedelimited pathway that probably involves G subunits (186,187). G subunits
target the I-II linker region and/or the COOH terminus of the -subunit of these
Ca2þ channels, decreasing the amount of current carried (188–190). D2 receptors in
striatal medium spiny neurons decrease L-type Ca2þ currents (191). This response
is also mediated by G subunits, although rather than being membrane delimited
the pathway involves G stimulation of cytosolic phospholipase C, mobilization of
Ca2þ, and activation of calcineurin (Figure 3).
The functional effects of this modulation are possibly to regulate neurotransmitter release when the N-type Ca2þ channel is targeted; thus, D2 receptor
activation of neostriatal interneurons inhibits the release of acetylcholine (192),
and D2-like receptor stimulation decreases glutamate release in striatum, presumably via effects on N-type Ca2þ channels (193,194). Inhibition of glutamate release
may implicate tonic D2 receptor activity in the prevention of excessive glutamate
release; together with D2 receptor inhibition of L-type channels in neostriatal
medium spiny neurons, this would be expected to promote the downstate in
neostriatal projection neurons. Facilitory effects of D1-like receptor stimulation
would take over when synchronized inputs arrive drive the cell into the upstate. In
this way, D2 receptor activation may serve as a gatekeeper over striatal upstates (85).
Voltage-dependent Ca2þ channels are inhibited by D2 receptors in the anterior
pituitary (128) and by the D3 receptor heterologously expressed in AtT-20 cells
(184); inhibition of Ca2þ channels in these cells would be expected to decrease
secretion of pituitary hormones.
G-Stimulated MAP Kinases
MAP kinases are components of parallel protein kinase cascades that transmit
signals from a variety of extracellular stimuli to the cell nucleus, thus participating
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Neve, Seamans, and Trantham-Davidson
in cell proliferation, differentiation, and survival (195). Like many other GPCRs,
including those coupled to Gi/o (195,196), activation of the D2 receptor stimulates
MAP kinases, including the two isozymes of extracellular signal-regulated kinase
(ERK) (197–204) and stress-activated protein kinase/Jun amino-terminal kinase
(SAPK/JNK) (199). D3 (205) and D4 (203,206) dopamine receptors also activate
ERK. D2-like receptors activate ERK in brain slices (35,207) and in rat brain after
administration of agonist in vivo (208).
Although the pathway from D2-like receptors to ERK has not been thoroughly
elucidated and may differ depending on cell type and receptor subtype, D2-like
receptor activation of ERK is frequently mediated by pertussis toxin-sensitive
G proteins (200,201,205,209), G (197,201,202), phosphatidylinositol 3-kinase
(200,205), Ras (199,206), and the MAP kinase kinase MEK (199,201,207,208). D2like receptor activation of ERK is in at least some cases mediated by transactivation
of a receptor tyrosine kinase (RTK), thus recruiting the RTK-signaling cascade in
response to dopamine. Although the epidermal growth factor receptor has
frequently been identified as an RTK that is transactivated by GPCRs (210,211),
transactivation of the platelet-derived growth factor receptor can be a necessary
intermediate step in the activation of ERK by recombinant and endogenous
D2 and D4 receptors (163,203,204). We have observed that the identity of the
RTK that is transactivated by D2-like receptors depends on cell type, with D2
receptor stimulation of ERK mediated by the platelet-derived growth factor
receptor in nonneuronal cells, but by the epidermal growth factor receptor in
neuroblastoma cells and primary neuronal cultures from embryonic rat neostriatum
(209). It is not clear which of the several identified mechanisms for RTK
transactivation (212) are used by D2-like receptors, although in some cells D2
receptor stimulation enhances a direct interaction between the D2 receptor and
the platelet-derived growth factor receptor (203) or the epidermal growth factor
receptor (209,213).
D2 receptor activation of ERK stimulates DNA synthesis and mitogenesis in
many different cell types (199,202,214,215). In post-mitotic neurons, activation
of MAP kinases is involved not only in cell survival and in synaptic plasticity
(216–218) but also in acute behavioral responses to dopamine receptor stimulation
(208). D2 receptor signaling to ERK in pituitary lactotrophs may be more
complicated; in both primary lactotrophs and a prolactin-secreting cell line, the
D2 receptor is reported to inhibit ERK, leading to suppression of prolactin promoter function (139). A conflicting report using a different prolactin-secreting
cell line describes D2 receptor stimulation of ERK leading to inhibition of cell
proliferation (219).
Epidermal growth factor receptors signal not only through a Ras-MEKERK pathway but also through a phosphoinositide 3-kinase ! protein kinase
B (Akt) pathway. D2 and D4 receptors activate Akt in several cell types with
neuronal characteristics and in immortalized dopaminergic neurons (206,213).
In PC12 cells expressing a recombinant D2 receptor, D2 receptor activation of Akt
is mediated by Src-dependent transactivation of the epidermal growth factor
receptor. This pathway mediates D2 receptor neuroprotection against oxidative
stress (213).
Dopamine Receptor Signaling
183
Other Signaling Pathways Regulated by D2-Like Receptors
D2-Like Receptor Regulation of Phospholipases
D2 receptors in neostriatal medium spiny neurons activate a cytosolic, Gstimulated form of phospholipase C, PLC1, causing inositol trisphosphate-induced
calcium mobilization that activates calcium-dependent proteins such as the protein
phosphatase calcineurin, ultimately reducing L-type Ca2þ currents (220). This
pathway may contribute to activation of both ERK and CREB by D2-like receptors
in neostriatal neurons (207) and also to the PKA-independent regulation of DARPP32 phosphorylation by D2-like receptors described above (158). This pathway and
the D4 receptor-stimulated transactivation of the platelet-derived growth factor
receptor leading to depression of NMDA receptor signaling in hippocampal neurons
have interesting similarities, such as dependence on G, phospholipase C, and
calcium mobilization, which are suggestive of a more general role for RTK transactivation in D2-like receptor signaling.
The D2 receptor potentiates arachadonic acid release induced by calciummobilizing receptors in heterologous expression systems (220–222), a response that
is mediated by cytosolic phospholipase A2 (223). The D4 receptor also activates
this pathway (223), whereas the D3 receptor has no effect or is inhibitory (224).
Although the response is inhibited by pertussis toxin, the lack of effect of cyclic AMP
and the sensitivity of cytosolic phospholipase A2 to G (225,226) suggest that
this is a G-mediated response. D2 receptor-stimulated arachidonate release in the
absence of a calcium-mobilizing agent has also been observed (227). Arachidonic
acid and its bioactive lipooxygenase and cyclooxygense metabolites (e.g., prostaglandin E2) have numerous effects on cellular function and may feed back to regulate
D2-like receptor signaling and uptake (228–231).
Many GPCRs, including the D2 receptor, stimulate phospholipase D, which
catalyzes the hydrolysis of phosphatidylcholine to form choline and phosphatidic
acid (232,233). The low molecular weight G protein RhoA is required for this D2
receptor-mediated response (234), and work with other phospholipase D-activating
GPCRs has identified a direct interaction between the receptors and two monomeric
G proteins RhoA and ARF (232). D2 receptor stimulation of phospholipase D is
not mediated by Gi/o, because stimulation is insensitive to pertussis toxin but does
require activation of protein kinase C" (233). Activation of G13, which in turn
stimulates the Rho guanine nucleotide exchange activator (p115RhoGEF), is a
mechanism by which some GPCRs activate phospholipase D (235–237).
D2-Like Receptor Regulation of Naþ Channels
D2-like receptor activation in the neostriatum exerts variable effects on Naþ
channels possibly via several intracellular signaling pathways. In the prefrontal
cortex, on the other hand, D2-like receptor stimulation does not appear to exert
a consistent or strong effect over Naþ channels in some studies (81, but see 238),
perhaps because D1-like receptors are somehow in a better position to control these
channels or simply more abundant. The strong effect of prefrontal cortical D2-like
184
Neve, Seamans, and Trantham-Davidson
receptors on other ion channels may reflect differences in scaffolding with these
channels.
Surmeier et al. (27,181) discovered that D2-like receptor stimulation can
either increase or decrease Naþ currents in neostriatal neurons, perhaps depending
on the subtype of D2-like receptors expressed by a given cell. Enhancement of
Naþ currents requires a soluble second messenger and may represent a process
reciprocal to attenuation of voltage-gated Naþ currents by D1 receptor-stimulated
activation of PKA and DARPP-32 (23,116). That is, the D2-like receptor stimulated
increase in Naþ current observed in a minority of neostriatal neurons may be due to
inhibition of adenylate cyclase and PKA, preventing phosphorylation of the channel.
In most D2 agonist-responsive neurons, D2-like receptor stimulation decreases Naþ
currents in a membrane-delimited manner (181) that may involve binding of G
subunits to the Naþ channels. The Naþ current attenuation involved a shift
in inactivation potential to more negative values, with no decrease in the peak
amplitude of the current. These results mimic the effects of inhibition of pertussis
toxin-sensitive G-proteins (presumably Gi/o) on recombinant Naþ channels in CHO
cells that are similar to the type expressed in the striatum (239).
D2-Like Receptor Regulation of Naþ/Hþ Exchange
The Naþ/Hþ exchangers are a family of integral membrane proteins that regulate
intracellular pH and transcellular Naþ absorption (240). Heterologously expressed
D2 (133), D3 (241,242), and D4 receptors (222) activate the widely expressed
Naþ/Hþ exchanger NHE1. Like GPCR activation of phospholipase D, D2
receptor activation of Naþ/Hþ exchange is insensitive to pertussis toxin in
some cell lines (133), and the G protein G13 can activate the exchanger via
Rho (243). It is of interest that several GPCR subtypes, including endogenous
D2-like receptors in primary lactotrophs, mediate pertussis toxin-insensitive
and cyclic AMP-independent inhibition of Naþ/Hþ exchanger activity (132,244).
Lin et al. (244) have proposed that a potential mechanism for this inhibition is
G12 competition for the interaction between G13 and p115RhoGEF. Naþ/Hþ
exchange is also inhibited by D1-like receptors by both cyclic AMP-dependent
and -independent mechanisms (115,245).
D2-Like Receptor Regulation of Receptor-Linked Ion Channels
Glutamatergic neurotransmission is enhanced in D2 receptor null mutant mice,
which probably reflects the loss of both presynaptic control of glutamate release and
postsynaptic inhibition of glutamatergic responses by the D2 receptor (246). D2-like
receptor stimulation decreases NMDA currents, but the mechanism for this effect
is still debated. One idea is that D2 stimulation results in changes in Kþ and Naþ
permeabilities that hyperpolarize cells and prevent the removal of the Mg2þ blockade
over these channels, resulting in a decrease in the open probability of the channel
(98). Another idea is that D2 stimulation causes dephosphorylation of the NR1
subunit by antagonizing D1-like receptor stimulation of the DARPP-32 signaling
Dopamine Receptor Signaling
185
cascade (92). In prefrontal cortex, the D4 receptor decreases NMDA currents by
a similar mechanism involving disinhibition of PP1 (162). Another means by which
D2 activation attenuates NMDA currents in hippocampus is via transactivation of
the platelet-derived growth factor receptor (163).
A consistent role for the D2 receptor has not been described for GABA transmission, perhaps because both D1-like and D2-like receptors modulate GABAergic
transmission by altering GABA release (247). In addition to decreasing the probability of GABA release in the prefrontal cortex, D2 receptor agonists reduce postsynaptic responsiveness to a GABAA agonist by a mechanism that includes
transactivation of the platelet-derived growth factor receptor (247,248). This mechanism is consistent with work showing that activation of the platelet-derived growth
factor receptor decreases GABAA currents via activation of phospholipase C and
subsequent mobilization of intracellular Ca2þ to alter the phosphorylation state
of the receptor (249).
Novel Protein–Protein Interactions Involved in D2-Like Receptor Signaling
D2-Like Receptor Signaling via Receptor Heteromerization
We have discussed some functional consequences of dopamine receptor heteromerization with ion channels (D1 and NMDA, D5 and GABAA), receptor tyrosine
kinases (D2/D4 and the epidermal growth factor and platelet-derived growth factor
receptors), and other dopamine receptor subtypes (D2 and D3) in other contexts
in this review. The D2 receptor can also participate in heteromers with other GPCRs
including the somatostatin receptor subtype SSTR5 (251), and the adenosine A2A
receptor (251,252). Intramembrane interactions of the D2 receptor with neurotensin
and metabotropic glutamate receptors are also potentially mediated by direct
receptor:receptor interactions (253), although competition for a limiting pool of
another receptor-interacting protein is another possible mechanism. The formation
of heteromers can be constitutive (252) or stimulated by the binding of ligands,
particularly agonists (250), and may underlie mutually inhibitory (253) or stimulatory (250) interactions. There is considerable behavioral and functional evidence
for interactions between brain dopamine and adenosine systems and between dopamine and somatostatin, and receptor heteromerization is likely to be a molecular
mechanism of these interactions (254).
Other Dopamine Receptor-Interacting Proteins That Modulate Signaling
A number of interactions between the third cytoplasmic loop of D2-like
receptors and other proteins are likely to influence D2-like receptor signaling. D2
and D3 receptors, but not D1 or D4 receptors, bind the actin-binding protein filamin
A, or ABP-280. Zhou and colleagues report that binding is to a segment in the
carboxyl terminus of the third cytoplasmic loop, where both D2 and D3 receptors
have a potential site of phosphorylation by PKC, and that D2 and D3 receptors
expressed in cells that lack ABP-280 have diminished ability to inhibit adenylate
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Neve, Seamans, and Trantham-Davidson
cyclase (255,256). Furthermore, PKC-catalyzed phosphorylation of the D2 receptor
on Ser358 may inhibit binding of ABP-280, thus attenuating D2 receptor signaling
(255). The third cytoplasmic loop of the D2 receptor includes a binding site for
spinophilin, a scaffolding protein that also binds and targets PP1 to dendritic spines
(257). PP1 anchoring by spinophilin is critical for modulation of glutamate receptor
activity by dopamine (100). Calmodulin binds in a calcium-dependent manner to the
amino terminal end of the D2 receptor third cytoplasmic loop and inhibits D2
receptor activation of, but not binding to, Gi (258). Proteins, such as Nck, Grb2,
and c-Src which contain Src homology 3 (SH3) domains, a modular protein-protein
interaction domain that is essential for the formation of functional signaling
complexes, bind to the third cytoplasmic loop of the D4 receptor, which has multiple
copies of the proline-rich SH3 binding motif (259). Several SH3 domain-containing
proteins also bind to the D3 receptor, although the site of binding has not been
identified (259,260). The functional role of SH3 protein binding to D2-like receptors
is unknown, although mutation of the SH3 binding motifs in the D4 receptor causes
constitutive internalization of the receptor (260), and binding of the protein tyrosine
kinase c-Src to other GPCRs has important consequences for receptor signaling and
desensitization (261).
CONCLUSION
Dopamine receptor signal transduction pathways are complex, so that just one
dopamine receptor subtype can activate multiple effectors by distinct or partially
overlapping pathways that have many points of intersection. One of the goals of this
review was to show how these effectors work in concert to alter cellular function in
response to dopamine receptor activation, an area in which considerable progress
has been made in recent years. On the other hand, much less is known about
how these cellular processes contribute to the function of neuronal networks and,
ultimately, to behavior. Another emerging area that is only touched on in this
review, despite its probable importance for GPCR function, is the role of proteinprotein interactions and signaling complexes in dopamine receptor signaling.
Elucidating the mechanisms and significance of receptor oligomerization, of
interactions with signal-switching proteins, such as calcyon, and of interactions
with scaffolding proteins that support the formation of the signaling complex and
target the complex to particular subcellular domains, will be crucial to understanding
dopamine receptor function at the molecular level.
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